Evidence Summary
Hepatitis B Virus Infection: Screening, 2014
May 27, 2014
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.
| Table of Contents |
|---|
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.
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.
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.
Scope of the Review
We developed a review protocol and analytic framework (Appendix Figure 1) that included the following key questions.
- What are the benefits of screening for HBV infection versus no screening in asymptomatic adolescents and adults on morbidity, mortality, and disease transmission?
- What are the harms of screening for HBV infection?
- How well do different screening strategies identify persons with HBV infection?
- In persons without evidence of HBV immunity, how effective is HBV vaccination at improving clinical outcomes?
- How effective is antiviral treatment at improving intermediate outcomes?
- How effective is antiviral treatment at improving health outcomes?
- What are the harms associated with antiviral treatment for HBV infection?
- 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.
Scope of the Review
We developed a review protocol and analytic framework (Appendix Figure 1) that included the following key questions.
- What are the benefits of screening for HBV infection versus no screening in asymptomatic adolescents and adults on morbidity, mortality, and disease transmission?
- What are the harms of screening for HBV infection?
- How well do different screening strategies identify persons with HBV infection?
- In persons without evidence of HBV immunity, how effective is HBV vaccination at improving clinical outcomes?
- How effective is antiviral treatment at improving intermediate outcomes?
- How effective is antiviral treatment at improving health outcomes?
- What are the harms associated with antiviral treatment for HBV infection?
- 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.
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.
1. Ioannou GN. Hepatitis B virus in the United States: infection, exposure, and immunity rates in a nationally representative survey. Ann Intern Med. 2011;154:319-28. [PMID: 21357909]
2. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008;48:335-52. [PMID: 18096267]
3. Centers for Disease Control and Prevention. Disease burden from viral hepatitis A, B, and C in the United States. In: Viral Hepatitis Statistics & Surveillance. Atlanta: Centers for Disease Control and Prevention; 2013. Accessed at www.cdc.gov/hepatitis/Statistics/index.htm on 11 May 2014.
4. Kowdley KV, Wang CC, Welch S, Roberts H, Brosgart CL. Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology. 2012;56:422-33. [PMID: 22105832]
5. Mitchell T, Armstrong GL, Hu DJ, Wasley A, Painter JA. The increasing burden of imported chronic hepatitis B—United States, 1974-2008. PLoS One. 2011;6:e27717. [PMID: 22163270]
6. Sorrell MF, Belongia EA, Costa J, Gareen IF, Grem JL, Inadomi JM, et al. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med. 2009;150:104-10. [PMID: 19124811]
7. Weinbaum CM, Williams I, Mast EE, Wang SA, Finelli L, Wasley A, et al; Centers for Disease Control and Prevention (CDC). Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57(RR-8):1-20. [PMID: 18802412]
8. Zanetti AR, Van Damme P, Shouval D. The global impact of vaccination against hepatitis B: a historical overview. Vaccine. 2008;26:6266-73. [PMID: 18848855]
9. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009; 50:661-2. [PMID: 19714720]
10. U.S. Preventive Services Task Force. Screening for Hepatitis B Virus Infection. Rockville, MD: U.S. Preventive Services Task Force; 2004.
11. U.S. Preventive Services Task Force. Screening for Hepatitis B Virus Infection: A Brief Evidence Update for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2004.
12. Chou R, Dana T, Bougatsos C, Blazina I, Zakher B, Khangura J. Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults: Systematic Review to Update the 2004 U.S. Preventive Services Task Force Recommendation. Rockville, MD: Agency for Healthcare Research and Quality; 2014.
13. U.S. Preventive Services Task Force. Screening for hepatitis B virus infection in pregnancy: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2009;150:869-73. [PMID: 19528565]
14. Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al; Methods Work Group, Third US Preventive Services Task Force. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20:21-35. [PMID: 11306229]
15. U.S. Preventive Services Task Force. Procedure Manual. AHRQ Publication no. 08-05118-EF. Rockville, MD: U.S. Preventive Services Task Force; 2008. Accessed at www.uspreventiveservicestaskforce.org/Page/Name/procedure-manual on 11 December 2014.
16. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-60. [PMID: 12958120]
17. Spenatto N, Boulinguez S, Mularczyk M, Molinier L, Bureau C, Saune K, et al. Hepatitis B screening: who to target? A French sexually transmitted infection clinic experience. J Hepatol. 2013;58:690-7. [PMID: 23220369]
18. Chen W, Gluud C. Vaccines for preventing hepatitis B in health-care workers. Cochrane Database Syst Rev. 2005:CD000100. [PMID: 16235273]
19. Szmuness W, Stevens CE, Harley EJ, Zang EA, Oleszko WR, William DC, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med. 1980;303:833-41. [PMID: 6997738]
20. Coutinho RA, Lelie N, Albrecht-Van Lent P, Reerink-Brongers EE, Stoutjesdijk L, Dees P, et al. Efficacy of a heat inactivated hepatitis B vaccine in male homosexuals: outcome of a placebo controlled double blind trial. Br Med J (Clin Res Ed). 1983;286:1305-8. [PMID: 6404440]
21. Francis DP, Hadler SC, Thompson SE, Maynard JE, Ostrow DG, Altman N, et al. The prevention of hepatitis B with vaccine. Report of the centers for disease control multi-center efficacy trial among homosexual men. Ann Intern Med. 1982;97:362-6. [PMID: 6810736]
22. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al; Adefovir Dipivoxil 438 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348:800-7. [PMID: 12606734]
23. Jonas MM, Kelly D, Pollack H, Mizerski J, Sorbel J, Frederick D, et al. Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B. Hepatology. 2008;47:1863-71. [PMID: 18433023]
24. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al; Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348: 808-16. [PMID: 12606735]
25. Zeng M, Mao Y, Yao G, Wang H, Hou J, Wang Y, et al. A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B. Hepatology. 2006;44:108-16. [PMID: 16799983]
26. Bayraktar Y, Uzunalimoglu B, Arslan S, Koseoglu T, Kayhan B, Telatar H. Effects of recombinant alpha interferon on chronic active hepatitis B: preliminary results. Gut. 1993;34:S101. [PMID: 8314468]
27. Hadziyannis S, Bramou T, Makris A, Moussoulis G, Zignego L, Papaioannou C. Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis type B. J Hepatol. 1990;11 Suppl 1:S133-6. [PMID: 2079571]
28. Lampertico P, Del Ninno E, Manzin A, Donato MF, Rumi MG, Lunghi G, et al. A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology. 1997;26:1621-5. [PMID: 9398007]
29. Müller R, Baumgarten R, Markus R, Schulz M, Wittenberg H, Hintsche-Kilger B, et al. Treatment of chronic hepatitis B with interferon alfa-2b. J Hepatol. 1990;11 Suppl 1:S137-40. [PMID: 2079572]
30. Perez V, Tanno H, Villamil F, Fay O. Recombinant interferon alfa-2b following prednisone withdrawal in the treatment of chronic type B hepatitis. J Hepatol. 1990;11 Suppl 1:S113-7. [PMID: 2079567]
31. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC Jr, Lindsay K, Payne J, et al. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med. 1990;323:295-301. [PMID: 2195346]
32. Sarin SK, Guptan RC, Thakur V, Malhotra S, Malhotra V, Banerjee K, et al. Efficacy of low-dose alpha interferon therapy in HBV-related chronic liver disease in Asian Indians: a randomized controlled trial. J Hepatol. 1996;24:391-6. [PMID: 8738724]
33. Waked I, Amin M, Abd el Fattah S, Osman LM, Sabbour MS. Experience with interferon in chronic hepatitis B in Egypt. J Chemother. 1990;2:310-8. [PMID: 2090770]
34. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology. 1999;29:971-5. [PMID: 10051505]
35. Liaw YF, Lin SM, Chen TJ, Chien RN, Sheen IS, Chu CM. Beneficial effect of prednisolone withdrawal followed by human lymphoblastoid interferon on the treatment of chronic type B hepatitis in Asians: a randomized controlled trial. J Hepatol. 1994;20:175-80. [PMID: 8006397]
36. Mazzella G, Saracco G, Festi D, Rosina F, Marchetto S, Jaboli F, et al. Long-term results with interferon therapy in chronic type B hepatitis: a prospective randomized trial. Am J Gastroenterol. 1999;94:2246-50. [PMID: 10445557]
37. Ali HY. Trial of lamivudine in hepatitis B surface antigen carriers with persistent hepatitis B core IgM antibody. Saudi Med J. 2003;24:996-9. [PMID: 12973486]
38. Bozkaya H, Yurdaydin C, Idilman R, Tüzün A, Cinar K, Erkan O, et al. Lamivudine treatment in HBeAg-negative chronic hepatitis B patients with low level viraemia. Antivir Ther. 2005;10:319-25. [PMID: 15865226]
39. Chan HL, Wang H, Niu J, Chim AM, Sung JJ. Two-year lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B: a double-blind, placebo-controlled trial. Antivir Ther. 2007;12:345-53. [PMID: 17591024]
40. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999;341:1256-63. [PMID: 10528035]
41. Lai CL, Ching CK, Tung AK, Li E, Young J, Hill A, et al. Lamivudine is effective in suppressing hepatitis B virus DNA in Chinese hepatitis B surface antigen carriers: a placebo-controlled trial. Hepatology. 1997;25:241-4. [PMID: 8985298]
42. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998;339:61-8. [PMID: 9654535]
43. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-31. [PMID: 15470215]
44. Tassopoulos NC, Volpes R, Pastore G, Heathcote J, Buti M, Goldin RD, et al. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/ hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology. 1999;29:889-96. [PMID: 10051494]
45. Yalçin K, Degertekin H, Kokoglu OF, Ayaz C. A three-month course of lamivudine therapy in HBeAg-positive hepatitis B patients with normal aminotransferase levels. Turk J Gastroenterol. 2004;15:14-20. [PMID: 15264116]
46. Yao G, Wang B, Cui Z, Yao J, Zeng M. A randomized double-blind placebo-controlled study of lamivudine in the treatment of patients with chronic hepatitis B virus infection. Chin Med J (Engl). 1999;112:387-91. [PMID: 11593504]
47. Murray KF, Szenborn L, Wysocki J, Rossi S, Corsa AC, Dinh P, et al. Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. Hepatology. 2012;56:2018-26. [PMID: 22544804]
48. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al; BEHoLD AI463022 Study Group. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001-10. [PMID: 16525137]
49. Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007;133:1437-44. [PMID: 17983800]
50. Chang TT, Chao YC, Gorbakov VV, Han KH, Gish RG, de Man R, et al. Results of up to 2 years of entecavir vs lamivudine therapy in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. J Viral Hepat. 2009;16:784-9. [PMID: 19457141]
51. Lai CL, Rosmawati M, Lao J, Van Vlierberghe H, Anderson FH, Thomas N, et al. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology. 2002;123:1831-8. [PMID: 12454840]
52. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al; BEHoLD AI463027 Study Group. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011-20. [PMID: 16525138]
53. Ren FY, Piao DM, Piao XX. A one-year trial of entecavir treatment in patients with HBeAg-positive chronic hepatitis B. World J Gastroenterol. 2007;13:4264-7. [PMID: 17696259]
54. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al; Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682-95. [PMID: 15987917]
55. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al; Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206-17. [PMID: 15371578]
56. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-55. [PMID: 19052126]
57. Yu HB, Liu EQ, Lu SM, Zhao SH. Treatment with peginterferon versus interferon in Chinese patients with hepatitis B. Biomed Pharmacother. 2010;64:559-64. [PMID: 20630699]
58. Lai CL, Lim SG, Brown NA, Zhou XJ, Lloyd DM, Lee YM, et al. A dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic hepatitis B virus infection. Hepatology. 2004;40:719-26. [PMID: 15349912]
59. Andreone P, Gramenzi A, Cursaro C, Biselli M, Cammà C, Trevisani F, et al. High risk of hepatocellular carcinoma in anti-HBe positive liver cirrhosis patients developing lamivudine resistance. J Viral Hepat. 2004;11:439-42. [PMID: 15357649]
60. Baltayiannis G, Katsanos K, Karayiannis P, Tsianos EV. Interferon-alpha therapy in HBeAg-negative chronic hepatitis B: a long-term prospective study from north-western Greece. Aliment Pharmacol Ther. 2006;24:525-33. [PMID: 16886919]
61. Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, et al; Italian Association for the Study of the Liver (AISF) Lamivudine Study Group, Italy. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology. 2004;40: 883-91. [PMID: 15382125]
62. Fattovich G, Giustina G, Realdi G, Corrocher R, Schalm SW. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology. 1997;26:1338-42. [PMID: 9362381]
63. Hui CK, Leung N, Shek WH, Zhang HY, Luk JM, Poon RT, et al; Hong Kong Liver Fibrosis Study Group. Changes in liver histology as a "surrogate" end point of antiviral therapy for chronic HBV can predict progression to liver complications. J Clin Gastroenterol. 2008;42:533-8. [PMID: 18344885]
64. Lampertico P, Del Ninno E, Viganó M, Romeo R, Donato MF, Sablon E, et al. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology. 2003;37:756-63. [PMID: 12668967]
65. Lau DT, Everhart J, Cleaner DE, Park Y, Vergalla J, Schmid P, et al. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology. 1997;113:1660-7. [PMID: 9352870]
66. Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996;334:1422-7. [PMID: 8618580]
67. Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J Hepatol. 2001;34:306-13. [PMID: 11281561]
68. Papatheodoridis GV, Manolakopoulos S, Touloumi G, Vourli G, Raptopoulou-Gigi M, Vafiadis-Zoumbouli I, et al; HEPNET. Greece Cohort Study Group. Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece Cohort Study. Gut. 2011;60:1109-16. [PMID: 21270118]
69. Shamliyan TA, Johnson JR, MacDonald R, Shaukat A, Yuan JM, Kane RL, et al. Systematic review of the literature on comparative effectiveness of antiviral treatments for chronic hepatitis B infection. J Gen Intern Med. 2011;26:326-39. [PMID: 21203860]
70. Miyake Y, Kobashi H, Yamamoto K. Meta-analysis: the effect of interferon on development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Gastroenterol. 2009;44:470-5. [PMID: 19308310]
71. Zhang QQ, An X, Liu YH, Li SY, Zhong Q, Wang J, et al. Long-term nucleos(t)ide analogues therapy for adults with chronic hepatitis B reduces the risk of long-term complications: a meta-analysis. Virol J. 2011;8:72. [PMID: 21324130]
72. Lai CL, Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology. 2013;57:399-408. [PMID: 22806323]
73. Wong GL, Yiu KK, Wong VW, Tsoi KK, Chan HL. Meta-analysis: reduction in hepatic events following interferon-alfa therapy of chronic hepatitis B. Aliment Pharmacol Ther. 2010;32:1059-68. [PMID: 20807216]
74. Jin H, Pan N, Mou Y, Wang B, Liu P. Long-term effect of interferon treatment on the progression of chronic hepatitis B: Bayesian meta-analysis and meta-regression. Hepatol Res. 2011;41:512-23. [PMID: 21501353]
75. Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol. 2010;53:348-56. [PMID: 20483498]
76. Woo G, Tomlinson G, Nishikawa Y, Kowgier M, Sherman M, Wong DK, et al. Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses. Gastroenterology. 2010;139:1218-29. [PMID: 20600036]
77. Liang J, Tang YF, Wu FS, Deng X. Entecavir versus lamivudine for the treatment of chronic hepatitis B: a systematic review. Pharmazie. 2012;67:883- 90. [PMID: 23210236]
78. Dakin H, Fidler C, Harper C. Mixed treatment comparison meta-analysis evaluating the relative efficacy of nucleos(t)ides for treatment of nucleos(t)ide-naive patients with chronic hepatitis B. Value Health. 2010;13:934-45. [PMID: 20825624]
79. Zhao SH, Liu EQ, Cheng DX, Li YF, Wang YL, Chen YL, et al. Comparison of entecavir and adefovir for the treatment of chronic hepatitis B. Braz J Infect Dis. 2012;16:366-72. [PMID: 22846126]
80. Chou R, Hartung D, Rahman B, Wasson N, Cottrell EB, Fu R. Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review. Ann Intern Med. 2013;158:114-23. [PMID: 23437439]
81. Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med. 1997;336:1855-9. [PMID: 9197213]
82. Lim SG, Mohammed R, Yuen MF, Kao JH. Prevention of hepatocellular carcinoma in hepatitis B virus infection. J Gastroenterol Hepatol. 2009;24:1352-7. [PMID: 19702903]
83. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:417-22. [PMID: 15042359]
84. Chen JG, Parkin DM, Chen QG, Lu JH, Shen QJ, Zhang BC, et al. Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen. 2003;10:204-9. [PMID: 14738659]
85. Lin SY, Chang ET, So SK. Why we should routinely screen Asian American adults for hepatitis B: a cross-sectional study of Asians in California. Hepatology. 2007;46:1034-40. [PMID: 17654490]
86. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-2. [PMID: 19714720]
87. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493-505. [PMID: 21767103]
88. Lai CL, Yuen MF. The natural history and treatment of chronic hepatitis B: a critical evaluation of standard treatment criteria and end points. Ann Intern Med. 2007;147:58-61. [PMID: 17606962]
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.
| 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.
M–H = Mantel–Haenszel.
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%.
HBeAg = hepatitis B e antigen; M–H = Mantel–Haenszel.
* Adefovir, 30 mg, vs. placebo.
† 68-wk data.
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%.
HBV = hepatitis B virus; M–H = Mantel–Haenszel.
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%.
HBsAg = hepatitis B surface antigen; M–H = Mantel–Haenszel.
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%.
M–H = Mantel–Haenszel.
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%.
| 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.
| 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.
| 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.
| 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.
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.
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.
* 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.
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.
HBV = hepatitis B virus; M–H = Mantel–Haenszel.
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.
M–H = Mantel–Haenszel.
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%.
M–H = Mantel–Haenszel.
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%.