Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force | Adolescent Medicine | JAMA | JAMA Network
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Figure 1.  Analytic Framework: Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults
Analytic Framework: Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults

Evidence reviews for the USPSTF use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a service. The questions are depicted by linkages that relate interventions and outcomes. For additional information see the USPSTF Procedure Manual.12 Anti-HBc indicates antibody to the hepatitis B core antigen; anti-HBs, hepatitis B surface antibody; HBeAg, hepatitis B e-antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

aDefined as testing for anti-HBs and HBsAg, with or without testing for anti-HBc. bDefined by a positive HBsAg result. Chronic HBV infection should be staged by assessment for hepatitis fibrosis/inflammation, HBV viral load, HBeAg status, antibody to HBeAg (anti-HBe) status, and liver function test results. Appropriate interventions depend on disease stage. cDefined as positive anti-HBs, negative HBsAg, and positive (cleared infection) or negative (seroprotection due to vaccination) anti-HBc test results. Patients who have positive anti-HBc results may benefit from education regarding risk of reactivation. dDefined as positive anti-HBc test results but negative anti-HBs and HBsAg test results and indicates prior HBV exposure or false-positive result. Patients who have positive isolated anti-HBc test results may benefit from education regarding risk of reactivation and, if immunocompromised, HBV DNA testing. HBV vaccination is recommended for patients with positive isolated anti-HBc test results who are from countries with low prevalence of HBV infection (eg, US) or who are immunocompromised. eDefined as negative anti-HBs, anti-HBc, and HBsAg test results. fSubpopulations of interest for key questions 4, 5, and 6 include those defined by age, race/ethnicity, sex, injection drug use status, HBV genotype, HBeAg status, fibrosis stage, ALT level, presence of nonalcoholic steatohepatitis, HBV DNA, and hepatitis D virus status.

Figure 2.  Literature Search Flow Diagram: Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults
Literature Search Flow Diagram: Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults

HCV indicates hepatitis C virus; KQ, key question.

aSome included studies overlap among the KQs.

Figure 3.  Antiviral Treatment vs Placebo or No Treatment on Intermediate Outcomes (HBeAg Loss; HBV DNA Loss or Virologic Suppression)
Antiviral Treatment vs Placebo or No Treatment on Intermediate Outcomes (HBeAg Loss; HBV DNA Loss or Virologic Suppression)

Dashed line indicates the overall effect. HBeAg indicates hepatitis B e-antigen; HBV, hepatitis B virus; NR, not reported.

Figure 4.  Antiviral Treatment vs Placebo or No Treatment on Intermediate Outcomes (ALT Level Normalization; Histologic Improvement)
Antiviral Treatment vs Placebo or No Treatment on Intermediate Outcomes (ALT Level Normalization; Histologic Improvement)

ALT indicates alanine aminotransferase; HAI, histology activity index.

Figure 5.  Antiviral Treatment vs Placebo or No Treatment on Health Outcomes
Antiviral Treatment vs Placebo or No Treatment on Health Outcomes

Dashed line indicates the overall effect.

Table.  Summary of Evidence
Summary of Evidence
Supplement.

eMethods 1. Literature Search Strategies

eMethods 2. Quality Assessment Criteria

eTable 1. HBV Screening Strategies—Study Characteristics

eTable 2. HBV Screening Strategies—Results

eTable 3. HBV Screening Strategies—Quality Assessment

eTable 4. Trials of HBV Antiviral Treatment Versus Placebo or No Treatment—Study Characteristics

eTable 5. Trials of HBV Antiviral Treatment Versus Placebo or No Treatment—Results

eTable 6. Trials of HBV Antiviral Treatment—Quality Assessment

eTable 7. Antiviral Treatment Versus Placebo or No Treatment on Intermediate Outcomes—Subgroup Analyses

eTable 8. Trials of HBV Preferred Versus Non-preferred Treatments—Study Characteristics

eTable 9. Trials of HBV Preferred Versus Non-preferred Treatments—Results

eTable 10. Entecavir Versus Lamivudine on Intermediate Outcomes—Subgroup Analyses

eTable 11. Cohort Studies of HBV Treatment—Study Characteristics

eTable 12. Cohort Studies of HBV Treatment—Results

eTable 13. Cohort Studies of HBV Treatment—Quality Assessment

eTable 14. Association Studies of HBV Intermediate and Health Outcomes—Study Characteristics

eTable 15. Association Studies of HBV Intermediate and Health Outcomes—Results

eTable 16. Association Studies of HBV Intermediate and Health Outcomes—Quality Assessment

eTable 17. Association Between Intermediate and Health Outcomes—Summary

eFigure 1. Antiviral Treatment Versus Placebo or No Treatment—HBeAg Seroconversion

eFigure 2. Antiviral Treatment Versus Placebo or No Treatment—HBsAg Loss

eFigure 3. Antiviral Treatment Versus Placebo or No Treatment—HBV DNA Loss + ALT Normalization

eFigure 4. Antiviral Treatment Versus Placebo or No Treatment—HBV DNA Loss + HBeAg Loss

eFigure 5. Preferred Versus Nonpreferred Treatment—HBeAg Seroconversion

eFigure 6. Preferred Versus Nonpreferred Treatment—HBV DNA Loss/Suppression

eFigure 7. Preferred Versus Nonpreferred Treatment—ALT Normalization

eFigure 8. Entecavir Versus Lamivudine—Histologic Improvement

eFigure 9. Antiviral Treatment Versus Placebo or No Treatment—Serious Adverse Effects

eFigure 10. Antiviral Treatment Versus Placebo or No Treatment—Any Adverse Effects

eFigure 11. Antiviral Treatment Versus Placebo or No Treatment—Nausea

eFigure 12. Antiviral Treatment Versus Placebo or No Treatment—Elevated Creatinine

eFigure 13. Antiviral Treatment Versus Placebo or No Treatment—Withdrawals Due to Adverse Effects

eFigure 14. Preferred Versus Nonpreferred Treatment—Serious Adverse Effects

eFigure 15. Preferred Versus Nonpreferred Treatment—Withdrawals Due to Adverse Effects

eFigure 16. Preferred Versus Nonpreferred Treatment—Any Adverse Effects

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US Preventive Services Task Force
Evidence Report
December 15, 2020

Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Author Affiliations
  • 1Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
  • 2Division of General Internal Medicine and Geriatrics; Oregon Health & Science University, Portland
  • 3Department of Family Medicine, Oregon Health & Science University, Portland
  • 4Division of Gastroenterology and Hepatology; Oregon Health & Science University, Portland
JAMA. 2020;324(23):2423-2436. doi:10.1001/jama.2020.19750
Abstract

Importance  A 2014 review for the US Preventive Services Task Force (USPSTF) found antiviral therapy for hepatitis B virus (HBV) infection associated with improved intermediate outcomes, although evidence on clinical outcomes was limited.

Objective  To update the 2014 HBV screening review in nonpregnant adolescents and adults to inform the USPSTF.

Data Sources  Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE (2014 to August 2019); with surveillance through July 24, 2020.

Study Selection  Randomized clinical trials (RCTs) on screening and antiviral therapy; cohort studies on screening, antiviral therapy clinical outcomes, and the association between achieving intermediate outcomes after antiviral therapy and clinical outcomes.

Data Extraction and Synthesis  One investigator abstracted data; a second investigator checked accuracy. Two investigators independently assessed study quality. Random-effects profile likelihood meta-analysis was performed.

Results  Thirty trials and 20 cohort studies, with a total of 94 168 participants, were included. No study directly evaluated the effects of screening for HBV infection vs no screening on clinical outcomes such as mortality, hepatocellular carcinoma, or cirrhosis. Screening strategies that focused on risk factors such as ever having immigrated from high-prevalence countries and demographic and behavioral risk factors would identify nearly all HBV infection cases. In 1 study (n = 21 008), only screening immigrants from high-prevalence countries would miss approximately two-thirds of infected persons. Based on 18 trials (n = 2972), antiviral therapy compared with placebo or no treatment was associated with greater likelihood of achieving intermediate outcomes, such as virologic suppression and hepatitis B e-antigen (HBeAg) or hepatitis B surface antigen loss or seroconversion; the numbers needed to treat ranged from 2.6 for virologic suppression to 17 for HBeAg seroconversion. Based on 12 trials (n = 4127), first-line antiviral therapies were at least as likely as nonpreferred therapies to achieve intermediate outcomes. Based on 16 trials (n = 4809), antiviral therapy might be associated with improved clinical outcomes, but data were sparse and imprecise. Nine cohort studies (n = 3893) indicated an association between achieving an intermediate outcome following antiviral therapy and improved clinical outcomes but were heterogeneous (hazard ratios ranged from 0.07 to 0.87). Antiviral therapy was associated with higher risk of withdrawal due to adverse events vs placebo or no antiviral therapy.

Conclusions and Relevance  There was no direct evidence for the clinical benefits and harms of HBV screening vs no screening. Antiviral therapy for HBV infection was associated with improved intermediate outcomes and may improve clinical outcomes.

Introduction

The overall prevalence of chronic hepatitis B virus (HBV) infection in the US was been estimated at about 0.3% in 2007 to 2012, or approximately 847 000 persons.1,2 People born in countries with a 2% or greater HBV prevalence accounted for 47% of chronic infections in the US, based on survey data published through 2010, and for 95% of chronic infections in the US, based on an analysis of cases during 1974 to 2008.3,4 Since 2010, an increase in acute and chronic HBV infection related to drug use in younger adults has been reported in several states.5-7

In 2014, the US Preventive Services Task Force (USPSTF) recommended screening for HBV infection in persons at high risk for infection (B recommendation); an HBV prevalence of 2% or greater was noted as a reasonable threshold for deciding to screen.8 This evidence report was conducted to update the 2014 review on HBV screening9,10 to inform the USPSTF for an updated recommendation statement.

Methods
Scope of the Review

Detailed methods and additional study details are available in the full evidence report.11 Figure 1 shows the analytic framework and key questions (KQs) that guided the review; the contextual questions that were not reviewed systematically are addressed in the full report.

Data Sources and Searches

Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched from 2014 to August 2019 (eMethods 1 the Supplement). Searches were supplemented by reference list review of relevant systematic reviews; studies from the prior USPSTF review9,13 that met inclusion criteria were carried forward. Ongoing surveillance was conducted to identify major studies published since August 2019 that may affect the conclusions or understanding of the evidence and the related USPSTF recommendation. The last surveillance was conducted on July 24, 2020, and identified no studies affecting review conclusions.

Study Selection

Two investigators independently reviewed titles, abstracts, and full-text articles using predefined eligibility criteria. The population for screening was asymptomatic adults and adolescents without prior HBV infection. For treatment, to evaluate patients more likely to be asymptomatic and identified by screening, inclusion was restricted to studies in which less than 20% of patients had cirrhosis at baseline (less than 30% for cohort studies that also controlled for fibrosis stage). Randomized clinical trials of screening, antiviral therapy vs placebo, and preferred (first-line) antiviral therapy (entecavir, tenofovir disoproxil fumarate [TDF], tenofovir alafenamide [TAF], pegylated interferon [adults], and nonpegylated interferon [children]) vs nonpreferred (adefovir, lamivudine, and telbivudine) antiviral therapy (according to recent guidelines)14 were included. Nonpegylated interferon in adults was included because there were few trials of pegylated interferon. Studies that compared the yield of alternative screening strategies, large (n >1000) cohort studies of antiviral treatment vs no treatment that controlled for potential confounders and evaluated clinical outcomes at 1 year or later, and cohort studies that reported adjusted risk estimates for the association between achieving intermediate outcomes following antiviral treatment and long-term clinical outcomes (mortality or morbidity) were also included.

Clinical outcomes were mortality or morbidity (cirrhosis, hepatocellular cancer, quality of life, HBV transmission, extrahepatic outcomes, or harms). Intermediate outcomes were virologic (HBV DNA [DNA]) suppression, histologic improvement, biochemical improvement (normalization of alanine aminotransferase [ALT] or aspartate aminotransferase levels, hepatitis B e-antigen [HBeAg] clearance [loss of HBeAg or seroconversion, defined as acquisition of antibody to HBeAg], and hepatitis B surface antigen [HBsAg] clearance [HBsAg loss or or seroconversion, defined as acquisition of antibody to HBsAg]). Studies that focused on patients previously treated, co-infected with HIV or with hepatitis C virus co-infection, transplant patients, and persons with advanced kidney disease were excluded.

Data Abstraction and Quality Rating

One investigator abstracted details about the study design, patient population, setting, interventions, analysis, follow-up, and results from each study. A second investigator reviewed abstracted data for accuracy. Two independent investigators assessed the quality of each study as good, fair, or poor using predefined criteria developed by the USPSTF (eMethods 2 in the Supplement).12 Discrepancies were resolved through a consensus process. In accordance with the USPSTF Procedure Manual,12 studies rated poor-quality because of critical methodological limitations were excluded.

Data Synthesis

Random-effects meta-analysis, stratified by antiviral drug or comparison (for head-to-head trials), was performed to summarize the proportion of patients experiencing intermediate outcomes, clinical outcomes, and harms using a profile likelihood model in Stata/IC 14.2 (StataCorp). When the profile likelihood model did not converge, the Dersimonian-Laird model was used instead. Statistical heterogeneity was assessed using the I2 statistic. Subgroup analyses were conducted on study quality, geographic setting, duration of follow-up, HBeAg status, immune tolerant or immune active phase of HBV infection,14 prior antiviral treatment status, and cirrhosis (excluded or included some [up to 20% of sample] with baseline cirrhosis) and interactions were assessed using a test for heterogeneity across subgroups. Meta-analysis was not performed for the association between achieving an intermediate outcome after antiviral therapy and clinical outcomes because of small numbers of studies. Graphical and statistical tests for small sample effects were not conducted because of fewer than 10 trials for most analyses and clinical heterogeneity (due to differences in the drugs evaluated and populations [eg, HBeAg status]) in analyses with more than 10 trials.15

All significance testing was 2-tailed; P ≤ .05 or less was considered statistically significant.

Results

Across all KQs, 30 randomized clinical trials16-44 (n = 7099), 17 cohort studies45-61 (n = 56 029), and 3 retrospective studies (n = 31 040)62-64 addressing the yield of alternative strategies were included (Figure 2). Twenty-two studies30-33,40-52,59-61,63,64 were new for this update, and 28 studies16-29,34-39,53-58,62 were carried forward from the previous review. Seventeen studies included in the prior USPSTF review were excluded for this update because the proportion of patients with cirrhosis at baseline was above the 20% threshold65-71 or the 30% threshold (for association studies),72-75 patients were antiviral therapy–experienced,76-78 or the studies were rated poor-quality.79-81

Benefits and Harms of Screening

Key Question 1. What are the benefits of screening for HBV infection in asymptomatic, nonpregnant adolescents and adults on morbidity, mortality, and disease transmission?

No study met inclusion criteria for this KQ.

Key Question 2. What are the harms of screening for HBV infection in asymptomatic, nonpregnant adolescents and adults (eg, labeling or anxiety)?

No study met inclusion criteria for this KQ.

Key Question 3. What is the yield (number of new diagnoses per tests performed) and sensitivity of alternative HBV screening strategies (eg, universal vs targeted screening or screening strategies based on alternative risk factors)?

Three fair-quality European studies (n = 30 040)62-64 retrospectively compared the yield of alternative screening strategies (eTables 1-3 in the Supplement). They found that screening based on the presence of any of multiple risk factors (ever having immigrated from high-prevalence countries, other demographic risk factors, and behavioral risk factors) would result in screening about two-thirds of the population and identify nearly all cases of HBV infection; the numbers needed to screen to identify 1 HBV infection ranged from 32 to 148. Screening only immigrants from high-prevalence (≥2%) countries was more efficient (number needed to screen, 19-71) and identified 85% to 99% of patients with HBV infection in higher-prevalence clinical settings but missed about two-thirds of HBV infections in a study64 conducted in primary care practices.

Benefits and Harms of Treatment

Key Question 4. How effective is antiviral treatment in improving intermediate outcomes among nonpregnant adolescents and adults with chronic HBV infection, including virologic suppression, histologic improvement, biochemical improvement, clearance of HBeAg (as indicated by loss of HBeAg or acquisition of the antibody to HBeAg), or clearance of HBsAg (as indicated by loss of HBsAg or acquisition of hepatitis B surface antibody)?

Antiviral Therapy vs Placebo or No Treatment

Eighteen trials (n = 2972) reported effects of antiviral therapy (entecavir, nonpegylated interferon alfa-2a or alfa-2b, adefovir, or lamivudine) vs placebo or no treatment on intermediate outcomes (eTables 4-5 in the Supplement).16-33 No trial evaluated pegylated interferon, tenofovir (TDF or TAF), or telbivudine. All trials included only adults. The duration of follow-up ranged from 1.8 to 86 months. All trials were rated fair-quality; methodological limitations included unclear reporting of randomization, allocation concealment, and blinding methods (eTable 6 in the Supplement).

Antiviral therapy, vs placebo or no antiviral therapy, was associated with increased likelihood of HBeAg loss (6 trials, n = 1121; risk ratio [RR], 1.91 [95% CI, 1.46 to 2.81]; I2 = 15%; absolute risk difference [ARD], 14% [95% CI, 5.8% to 23%]) (Figure 3A),18,24,25,29-31 HBeAg seroconversion (4 trials, n = 1104; RR, 2.11 [95% CI, 1.30 to 3.55]; I2 = 0%; ARD, 6.2% [95% CI, 2.4% to 10%]) (eFigure 1 in the Supplement),18,24,28,29 HBsAg loss (3 trials, n = 714; RR, 4.63 [95% CI, 1.10 to 19.55]; I2 = 70%; ARD, 8.2% [95% CI, –2.6% to 19%]) (eFigure 2 in the Supplement),25,27,33 HBV DNA suppression vs placebo (13 trials, n = 2522; RR, 4.39 [95% CI, 2.61 to 7.39]; I2 = 86%; ARD, 39% [95% CI, 24% to 53%]) (Figure 3B),17-20,24,25,27-33 normalization of ALT levels (11 trials, n = 2044; RR, 2.62 [95% CI, 2.22 to 3.10]; I2 = 0%; ARD, 24% [95% CI, 7.8% to 39%] (Figure 4A),16-20,23-25,29,30,33 and histologic improvement (6 trials, n = 1057; RR, 2.00 [95% CI, 1.63 to 2.41]; I2 = 0%; ARD, 28% [95% CI, 22% to 34%]; (Figure 4B).17-20,24,32

Antiviral therapy was also associated with increased likelihood of the composite outcomes HBV DNA suppression plus normalization of ALT levels (3 trials, n = 286; RR, 6.30 [95% CI, 3.06 to 13.11]; I2 = 0%; ARD, 48% [95% CI, 29% to 61%]) (eFigure 3 in the Supplement)17,22,27 and HBeAg loss or seroconversion plus HBV DNA suppression (4 trials, n = 623; RR, 2.36 [95% CI, 1.44 to 4.28]; I2 = 0%; ARD, 12% [95% CI, 4.8% to 24%]) (eFigure 4 in the Supplement).20,23,28,31 The estimates stratified by each individual drug consistently favored antiviral therapy, except when there was marked imprecision. For HBV DNA suppression, there were statistically significant interactions between geographic region, duration of follow-up, and HBeAg status and antiviral therapy effects, but results favored antiviral therapy in each of these subgroups (eTable 7 in the Supplement). For normalization of ALT levels, there was a statistically significant interaction between HBeAg status and antiviral therapy effects, but only 1 trial excluded HBeAg-positive patients. Otherwise, there were no significant interactions between geographic region, prior antiviral treatment status, follow-up duration, HBeAg status, or immune tolerant phase and effects on intermediate outcomes.

Preferred vs Nonpreferred Regimens

Twelve trials (reported in 11 publications) (n = 4127) compared preferred (entecavir, TDF, or pegylated interferon alfa-2a) vs nonpreferred (lamivudine, telbivudine, or adefovir) antiviral regimens on intermediate outcomes (eTables 8-9 in the Supplement).34-44 Duration of follow-up ranged from 3.7 to 22 months. Five trials were rated good-quality,34,35,37,40,43 and the others were rated fair-quality because of unclear or no blinding of outcome assessors, care providers, or patients (eTable 6 in the Supplement).

Preferred antiviral therapy, vs nonpreferred antiviral therapy, was associated with similar or increased likelihood of HBeAg loss (3 trials, n = 813),36,37,40 HBeAg seroconversion (7 trials, n = 2173) (eFigure 5 in the Supplement),36-39,43,44,82 HBsAg loss or seroconversion (3 trials, n = 1492),34,37,38 virologic suppression (12 trials, n = 3983) (eFigure 6 in the Supplement),35-44,82 normalization of ALT levels (11 trials, n = 3875) (eFigure 7 in the Supplement),35-41,43,44,82 and histologic improvement (2 trials, n = 1211) (eFigure 8 in the Supplement).35,82 However, estimates for some head-to-head comparisons were based on few trials and were imprecise. Subgroup analyses found no statistically significant interactions between HBeAg status or duration of follow-up and effects of entecavir vs lamivudine on normalization of ALT levels or virologic suppression (eTable 10 in the Supplement). Otherwise, subgroup analyses were not performed because of small numbers of trials.

Key Question 5. How effective is antiviral treatment in improving health outcomes among nonpregnant adolescents and adults with chronic HBV infection?

Antiviral Therapy vs Placebo or No Treatment

Seven randomized trials of antiviral therapy vs placebo or no treatment (n = 1042) reported effects on clinical outcomes (eTables 4-5 in the Supplement).17,18,20,22,23,25,31 None of the trials reported effects on quality of life, risk of HBV disease transmission, or extrahepatic outcomes. The trials were not designed to evaluate effects on clinical outcomes and there were a total of 23 cases of incident cirrhosis in 2 trials,23,2513 cases of hepatocellular carcinoma in 4 trials,17,22,23,25 and 8 deaths in 3 trials23,25,31 (2 other trials that reported mortality recorded no deaths).18,20 The duration of follow-up ranged from 11 to 86 months.

Antiviral therapy was associated with decreased risk of mortality vs placebo or no therapy (3 trials, n = 349; RR, 0.15 [95% CI, 0.03 to 0.69]; I2 = 0%; ARD, –0.3% [95% CI, –1.7% to 0.8%]) (Figure 5A); all of the trials reporting mortality evaluated nonpegylated interferon.23,25,31 Pooled estimates for incident cirrhosis (2 trials, n = 165; RR, 0.72 [95% CI, 0.29 to 1.77]; I2 = 0%) (Figure 5B)23,25 and hepatocellular carcinoma (4 trials, n = 343; RR, 0.60 [95% CI, 0.16 to 2.33]; I2 = 20%) (Figure 5C)17,22,23,25 favored antiviral therapy over placebo or no therapy, but differences were not statistically significant.

Seven fair-quality cohort studies (n ≈ 50 912) evaluated effects of antiviral therapy vs no therapy on mortality or hepatocellular carcinoma after controlling for potential confounders (eTables 11-13 in the Supplement).45-51 Follow-up ranged from 2.7 to 8.9 years. Three studies appeared to examine overlapping populations from a Taiwanese administrative database.48,50,51 Studies typically adjusted for age, sex, and fibrosis stage; some studies also adjusted for HBV DNA level, ALT level, or medical comorbidities.

Antiviral therapy was consistently associated with decreased risk of hepatocellular carcinoma vs no antiviral therapy in 2 US studies (n = 2671; adjusted hazard ratio [HR], 0.39 [95% CI, 0.27 to 0.56] after 5.2 years,45 and n=1302; adjusted HR, 0.24 [95% CI, to 0.10 to 0.58] after 8.9 years)46 and in 5 studies conducted in Asian populations (n =  ≈ 44 576 [excluding potentially overlapping populations], adjusted HRs ranged from 0.37 at 2.7 years’ follow-up to 0.64 at 5.3 years’ follow-up).47-51 A study conducted in Taiwan found antiviral therapy associated with decreased risk of mortality (n = 3088; adjusted HR, 0.58 [95% CI, 0.43 to 0.79]).50

Preferred vs Nonpreferred Regimens

Nine trials (n = 3767, reported in 8 publications) evaluated effects of preferred vs nonpreferred antiviral therapy on clinical outcomes (mortality, cirrhosis, hepatocellular carcinoma) (eTables 8-9 in the Supplement).34,35,37-41,43 The trials were not designed to evaluate clinical outcomes and reported very small numbers of events, resulting in very imprecise estimates.

Key Question 6. What are the harms associated with antiviral treatment in nonpregnant adolescents and adults with chronic HBV infection?

Antiviral Therapy vs Placebo or No Treatment

There were no statistically significant differences between antiviral therapy vs placebo or no antiviral therapy in risk of serious adverse events (4 trials, n = 802; RR, 0.92 [95% CI, 0.45 to 1.85]; I2 = 0%) (eFigure 9 in the Supplement),17,19,20,27 any adverse event (5 trials, n = 1290; RR, 1.01 [95% CI, 0.90 to 1.11]; I2 = 0%) (eFigure 10 in the Supplement),19,20,27,29,31 nausea (3 trials; RR, 0.80 [95% CI, 0.48 to 2.10]; I2 = 0%) (eFigure 11 in the Supplement),24,27,29 or elevated creatinine levels (3 trials; RR, 1.27 [95% CI, 0.31 to 3.55]; I2 = 0%) (eFigure 12 in the Supplement).17,18,20 However, estimates were imprecise. The estimate for withdrawal due to adverse events suggested increased risk (3 trials, n = 505; RR, 4.44 [95% CI, 0.95 to 20.77]; I2 = 0%) (eFigure 13 in the Supplement),22,24,27 which was highest in a trial of interferon alfa-2a (n = 42; 23.8% vs 0%; RR, 11.00 [95% CI, 0.65 to 187.17]).22 Another trial found interferon associated with markedly increased risk of any adverse event (89.6% vs 0%; RR, 107.14 [95% CI, 6.78 to 1694.36]).31 A cohort study (n = 1224) of Asian patients in the US found neither TDF nor entecavir associated with increased risk of osteopenia or osteoporosis compared with no therapy, although estimates were imprecise (adjusted HR, 0.74 [95% CI, 0.34 to 1.59] and 0.98 [95% CI, 0.51 to 1.90], respectively); fracture risk was not assessed.

Preferred vs Nonpreferred Regimens

There were no statistically significant differences between entecavir vs lamivudine or tenofovir vs adefovir in risk of serious adverse events (7 trials, n = 3136) (eFigure 14 in the Supplement),35,38,40,41,43,82 withdrawal due to adverse events (7 trials, n = 3223) (eFigure 15 in the Supplement),35,36,38,40,41,43,82 or any adverse event (7 trials, n = 3223) (eFigure 16 in the Supplement).35,36,38,40,41,43,82 However, estimates were imprecise. One trial (n = 543) found pegylated interferon alfa-2a associated with increased risk of serious adverse events (RR, 2.41 [95% CI, 0.86 to 6.74]), withdrawal due to adverse events (RR, 4.01 [95% CI, 0.86 to 18.73]), and any adverse event (RR, 1.58 [95% CI, 1.41 to 1.78]) vs lamivudine, though only the estimate for any adverse event was statistically significant.37 One small trial (n = 44) found entecavir associated with increased risk of any adverse event vs telbivudine, but the estimate was imprecise (RR, 1.58 [95% CI, 0.86 to 2.91]).42 Three head-to-head trials reported too few cases of elevated creatinine levels to determine effects of preferred vs nonpreferred therapy.38,41 No trial compared preferred vs nonpreferred antiviral therapy for bone adverse events.

Key Question 7. What is the association between improvements in intermediate outcomes as a result of antiviral treatment of chronic HBV infection and reduction in risk of HBV-related adverse health outcomes?

Nine fair-quality studies evaluated the association between improvement vs no improvement in intermediate outcomes following antiviral therapy for chronic HBV infection and clinical outcomes (eTables 14-16 in the Supplement). Sample sizes ranged from 63 to 1531 patients (total n = 3893), and the duration of follow-up ranged from 3.2 to 9.9 years.

Variability in patient populations (eg, HBeAg status and prevalence of cirrhosis at baseline), intermediate and clinical outcomes evaluated, and methodological limitations made it difficult to draw strong conclusions regarding the association between achieving intermediate outcomes after antiviral treatment and improvement in clinical outcomes (eTable 17 in the Supplement). However, across intermediate and clinical outcome comparisons, estimates of risk consistently favored achieving the intermediate outcomes and reduced risk of mortality (1 study, n = 103),55 hepatocellular carcinoma (4 studies, n = 3326),58-61 cirrhosis (1 study, n = 233),60 and composite clinical outcomes (6 studies, n = 1311),53-57,59 although some estimates were not statistically significant. The composite clinical outcomes consisted of various combinations of mortality, hepatocellular carcinoma, hepatic decompensation and associated complications, and liver transplant.

Discussion

The findings in this evidence report are summarized in the Table. The USPSTF previously determined that HBV screening tests are highly accurate.83 Studies in this review found that screening strategies that focused on patients with a variety of risk factors (immigration from high-prevalence country, other demographic risk factors, and/or behavioral risk factors) would identify nearly all cases of HBV infection while screening about two-thirds of the population.62-64 The number needed to screen to identify 1 HBV infection ranged from 32 to 148. A more focused strategy of only screening immigrants from high-prevalence countries would be more efficient (number needed to screen, 16-71), but missed about two-thirds of infected persons in 1 study64 conducted in primary care practices. The studies applied screening strategies retrospectively and were conducted in Europe, including some studies of high–HBV prevalence populations, which might limit applicability to primary care settings in the US.

As in the previous USPSTF review, randomized trials found antiviral therapy to be associated with increased likelihood of achieving various intermediate outcomes vs placebo or no treatment for achieving various intermediate outcomes. The numbers needed to treat to achieve 1 intermediate outcome ranged from 2.6 for HBV DNA suppression to 17 for HBeAg seroconversion. Results were generally consistent when analyses were stratified by individual drug, although some estimates were imprecise and not statistically significant. Although this update focused on US Food and Drug Administration–approved antiviral therapies, almost all of the placebo-controlled trials evaluated therapies classified as nonpreferred in current guidelines.14 However, the effectiveness of preferred therapies is supported by head-to-head trials, which found entecavir, TDF, and pegylated interferon associated with greater or similar likelihood of achieving various intermediate outcomes vs nonpreferred therapies. Effects of antiviral therapies were generally consistent when trials were stratified according to HBeAg status or whether some patients with cirrhosis were included.

As in the prior USPSTF review, antiviral therapy was not associated with an increased risk of serious adverse events or experiencing any adverse event vs placebo. Interferon therapy was associated with an increased risk of withdrawal due to adverse events, and pegylated interferon alfa-2a was associated with increased risk of serious adverse events and withdrawal due to adverse events vs lamivudine, consistent with known adverse effects of interferon-based therapies. Data on risks of kidney and bone adverse events were limited but did not indicate increased risk; this included the antiviral TDF, which has been associated with bone and kidney toxicities in some conditions.84 In general, adverse events associated with antiviral therapy, including interferon-based therapies, are self-limited and resolve following discontinuation of the drug.

Data from randomized trials on effects of antiviral therapy vs placebo or no therapy on clinical outcomes remains sparse. The trials were not designed to assess these outcomes because of small sample sizes and insufficient duration of follow-up. Although antiviral therapy was associated with decreased risk of mortality, the estimate was based on 3 trials of nonpegylated interferon with a total of 8 deaths. Antiviral therapy might be associated with decreased risk of cirrhosis and hepatocellular carcinoma, but estimates were imprecise and not statistically significant. Cohort studies found a consistent association between receipt of antiviral therapy and decreased risk of hepatocellular carcinoma. Most of the cohort studies were conducted in Asia, although studies conducted in the US reported findings consistent with those from the Asian studies. No trial evaluated effects of antiviral therapy on quality of life, risk of HBV transmission, or extrahepatic manifestations of HBV infection.

As in the prior USPSTF review, observational studies generally found an association between achieving an intermediate outcome and reduced risk of mortality, hepatocellular carcinoma, cirrhosis, or a composite clinical outcome. However, results were not statistically significant in all studies. In addition, differences across studies in the intermediate and clinical outcomes evaluated, variability in patient populations (eg, with regard to HBeAg status, ALT levels, or HBV DNA levels) and methodological limitations precluded strong conclusions.

Research is needed to clarify effects of screening and subsequent interventions on clinical outcomes and to identify optimal screening strategies. In addition, no study meeting inclusion criteria evaluated adolescents and the trials focused on treatment of patients with immune active HBV infection, with very little data for immune tolerant phase infection. No trial evaluated the preferred antiviral TAF, which was FDA-approved for chronic HBV infection in 2016 and may have fewer kidney and bone toxicities compared with TDF.85

Limitations

This review has several limitations. First, evidence from placebo-controlled trials of preferred antiviral therapy was limited; therefore, head-to-head trials of preferred vs nonpreferred antiviral therapy were also included. Second, studies included in the prior USPSTF review were excluded if they were rated poor-quality or exceeded predefined thresholds for the proportion of patients with baseline cirrhosis or prior antiviral therapy, reducing the available evidence base. However, these exclusions strengthened the quality and applicability of the reviewed evidence to screening populations. Third, observational studies were included on the effects of antiviral therapy on long-term clinical outcomes and the association between achieving an intermediate outcome after antiviral therapy and clinical outcomes.86 To reduce potential confounding, inclusion was restricted to studies that controlled for potential confounders. Fourth, studies conducted in countries where the prevalence, characteristics, and natural history of HBV infection may differ from those in the US were included. However, findings were similar for studies conducted in settings with low or high HBV prevalence and for studies conducted in Asia and the US. Fifth, the review did not include a search for studies published only as abstracts and could not formally assess for publication bias with graphical or statistical methods because of small numbers of studies.15

Conclusions

There was no direct evidence for the clinical benefits and harms of HBV screening vs no screening. Antiviral therapy for chronic HBV infection was associated with improved intermediate outcomes and may improve clinical outcomes.

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Article Information

Corresponding Author: Roger Chou, MD, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code BICC, Portland, OR 97239 (chour@ohsu.edu).

Accepted for Publication: September 21, 2020.

Author Contributions: Dr Chou had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Chou, Jou.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Chou, Bougatsos, Selph, Grusing.

Critical revision of the manuscript for important intellectual content: Chou, Blazina, Holmes, Jou.

Statistical analysis: Chou, Blazina.

Obtained funding: Chou.

Administrative, technical, or material support: Blazina, Bougatsos, Grusing.

Supervision: Chou, Bougatsos, Jou.

Conflict of Interest Disclosures: Dr Chou reported receiving grants from the World Health Organization. No other disclosures were reported.

Funding/Support: This research was funded under contract HHSA290201500009-I, Project ID 038-606-014, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF).

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight; reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We thank the following individuals for their contributions to this project: AHRQ Medical Officers Kathleen Irwin, MD, MPH, and Tracy Wolff, MD, MPH; as well as the USPFTF. We also acknowledge past and current USPSTF members who contributed to topic deliberations. The USPSTF members, external reviewers, and federal partner reviewers did not receive financial compensation for their contributions.

Additional Information: A draft version of this evidence report underwent external peer review from 3 content experts (David E. Kaplan, MD, MSc, Perelman School of Medicine, University of Pennsylvania; Rebecca L. Morgan, MPH, PhD, McMaster University; John W. Ward, MD, Task Force for Global Health Inc), 2 federal partners representing the Centers for Disease Control and Prevention, and 1 federal partner each representing the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute on Drug Abuse. Comments were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence report.

Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying USPSTF Recommendation Statement. It did not undergo additional peer review after submission to JAMA.

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