Screening for Hepatitis B Virus Infection in Adolescents and Adults -- Adolescents and adults at increased risk for infection


General

Grade: B The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.

Specific Recommendations

The USPSTF recommends screening for hepatitis B virus (HBV) infection in adolescents and adults at increased risk for infection. See the Practice Considerations section for a description of adolescents and adults at increased risk for infection.

Frequency of Service

For patients with negative HBsAg results who have not received the HBV vaccine series, periodic screening may be useful for those who report continued risk for acquiring HBV transmission, such as persons who continue to inject drugs and men who have sex with men. Clinical judgment should be used to determine screening frequency. The USPSTF found no evidence to determine optimal screening intervals.

Risk Factor Information

Persons from such risk groups include persons who have injected drugs in the past or currently; men who have sex with men; persons with HIV; and sex partners, needle-sharing contacts, and household contacts of persons known to be HBsAg positive. Some persons with combinations of risk factors who are not members of risk factor groups listed above may also be at increased risk for HBV infection.


Clinical

Practice Considerations

Patient Population Under Consideration

This recommendation applies to asymptomatic, nonpregnant adolescents and adults at increased risk for HBV infection, including those who were vaccinated before being screened for HBV infection. The USPSTF has made a separate recommendation on screening in pregnant women.8

Assessment of Risk

The risk for HBV infection varies substantially by country of origin in non–US-born persons living in the US. Persons born in countries with a prevalence of hepatitis B surface antigen (HBsAg) of 2% or greater (Table 2, Figure) account for the majority of cases of new chronic HBV infection in the US; most persons in these countries acquired HBV infection from perinatal transmission.2 Persons born in the US with parents from regions with higher prevalence are also at increased risk of HBV infection during birth or early childhood, particularly if they do not receive appropriate passive and active immunoprophylaxis (and antiviral therapy for pregnant women with a high viral load) (Figure).11-13 The CDC classifies HBV endemicity levels by prevalence of positive HBsAg (high [8%], moderate [2%-7%], or low [<2%]) (Figure). The estimated prevalence of HBV infection in the general US population is 0.3% to 0.5%,8,9,11,12,14,15 which makes it reasonable to screen adolescents and adults born in countries or regions with an HBsAg prevalence of 2% or greater (regardless of vaccination history in their country of origin) and adolescents and adults born in the US who did not receive the HBV vaccine as infants and whose parents were born in regions with an HBsAg prevalence of 8% or greater (regardless of their biological mother’s HBsAg status).

HBV screening should also be offered to other risk groups defined by clinical and behavioral characteristics in which prevalence of positive HBsAg is 2% or greater. Persons from such risk groups include persons who have injected drugs in the past or currently; men who have sex with men; persons with HIV; and sex partners, needle-sharing contacts, and household contacts of persons known to be HBsAg positive2,3,9,12-14,16,17 (Table 3). Some persons with combinations of risk factors who are not members of risk factor groups listed above may also be at increased risk for HBV infection. Clinicians should therefore consider the populations they serve when making screening decisions.

Screening Tests

Screening for hepatitis B should be performed with HBsAg tests approved by the US Food and Drug Administration, followed by a confirmatory test for initially reactive results.2,18

A positive HBsAg result indicates chronic or acute infection. Serologic panels performed concurrently with or after HBsAg screening allow for diagnosis and to determine further management. (See the Additional Tools and Resources section for serologic test interpretation.)

Screening Intervals

For patients with negative HBsAg results who have not received the HBV vaccine series, periodic screening may be useful for those who report continued risk for acquiring HBV transmission, such as persons who continue to inject drugs and men who have sex with men. Clinical judgment should be used to determine screening frequency. The USPSTF found no evidence to determine optimal screening intervals.

Treatment

Persons with testing results indicative of acute or chronic HBV infection generally receive education about reducing the risk of transmission to others (eg, during childbirth or with sex and needle-sharing partners and household contacts).20 Between 20% and 40% of patients with chronic HBV infection will require treatment4 (see the Additional Tools and Resources section for information on treatment). Several antiviral medications are approved by the US Food and Drug Administration for treatment of chronic HBV infection.21

Implementation

Many persons at risk for HBV infection are not screened or vaccinated.4 For example, approximately 11% to 67% of non–US-born persons and 28% to 52% of men who have sex with men have undergone HBV screening.4 Low uptake of screening may be related to several barriers, including language, lack of awareness about HBV, limited access to health care, inability to access affordable treatment, stigmatization, concerns about suspension from jobs and other communal activities, and patients’ concerns about reporting and follow-up of screening results by public health authorities that may involve notification of close contacts.4,14,22-24 When offering screening, clinicians should understand the positive and negative implications of reporting (as required by most US jurisdictions25), case investigations, and contact notification.24,26

Additional Tools and Resources

Several tools may help clinicians implement this screening recommendation. The CDC provides the following tools.

Other Related USPSTF Recommendations

Other related USPSTF recommendations are available at https://www.uspreventiveservicestaskforce.org/. These include screening for HBV infection during pregnancy;8 screening for hepatitis C virus infection in adults aged 18 to 79 years;27 screening for HIV in adolescents and adults aged 15 to 65 years;28 and behavioral counseling to prevent sexually transmitted infections.29


Rationale

Importance

An estimated 862,000 persons in the US are living with chronic infection with hepatitis B virus (HBV).1 Persons born in regions with a prevalence of HBV infection of 2% or greater, such as countries in Africa and Asia, the Pacific Islands, and parts of South America, often become infected at birth and account for up to 95% of newly reported chronic infections in the US. Other high-prevalence populations include persons who inject drugs; men who have sex with men; persons with HIV infection; and sex partners, needle-sharing contacts, and household contacts of persons with chronic HBV infection.2

According to the Centers for Disease Control and Prevention (CDC), an estimated 68% of people with chronic hepatitis B are unaware of their infection,3 and many remain asymptomatic until onset of cirrhosis or end-stage liver disease.4,5 This contributes to delays in medical evaluation and treatment and ongoing transmission to sex partners and persons who share objects contaminated with blood or other bodily fluids that contain HBV.3,6 From 15% to 40% of persons with chronic infection develop cirrhosis, hepatocellular carcinoma, or liver failure, which lead to substantial morbidity and mortality.4

USPSTF Assessment of Magnitude of Net Benefit

The USPSTF concludes with moderate certainty that screening for HBV infection in adolescents and adults at increased risk for infection has moderate net benefit.

See Table 1 for more information on the USPSTF recommendation rationale and assessment.

For more details on the methods the USPSTF uses to determine the net benefit, see the USPSTF Procedure Manual.7

Table 1. Summary of USPSTF Rationale

Rationale Nonpregnant adolescents and adults at increased risk
Detection Adequate evidence that the identification of HBV infection is accurate based on laboratory-based immunoassays for detecting hepatitis B surface antigen (HBsAg), with reported sensitivity and specificity exceeding 98%.
Benefits of early detection and intervention
  • Inadequate direct evidence on benefits of screening on health outcomes due to lack of studies.
  • Convincing evidence that antiviral treatment of patients with chronic HBV infection is effective at improving intermediate outcomes, including hepatitis B e-antigen (HBeAg) loss and virologic suppression.
  • Adequate evidence from clinical trials and cohort studies that antiviral treatment of patients with chronic HBV infection improves health outcomes, such as reduced risk of mortality or hepatocellular carcinoma.
  • Adequate evidence that improvements in intermediate outcomes of chronic HBV infection related to antiviral treatment (such as HBeAg clearance and virologic suppression) are associated with reduced risk of adverse health outcomes (such as cirrhosis and hepatocellular carcinoma).
Harms of early detection and intervention
  • Inadequate direct evidence on the harms of screening for HBV infection due to lack of studies.
  • Adequate evidence to bound the harms of screening as small to none based on the nature of the intervention and the low likelihood of serious harms. (When direct evidence is limited, absent, or restricted to select populations or clinical scenarios, the USPSTF may place conceptual upper or lower bounds on the magnitude of benefit or harms.)
  • Adequate evidence that the magnitude of harms of treatment is small based on several trials showing that risks of adverse events, nausea, and diarrhea are not significantly greater in persons receiving treatment than in persons receiving placebo or no treatment, and that some adverse events resolve after discontinuing therapy.
USPSTF assessment Moderate certainty that screening for HBV infection in nonpregnant adolescents and adults at increased risk for infection has a moderate net benefit, given the accuracy of screening tests and the effectiveness of antiviral treatment.

Abbreviations: HBV, hepatitis B virus; USPSTF, US Preventive Services Task Force.


Others

Supporting EvidenceScope of Review The USPSTF commissioned a systematic evidence review to update and expand on its prior review on screening for HBV infection in persons at increased risk.31In the current review,11,19 the USPSTF examined evidence from new randomized clinical trials and cohort studies published from 2014 to August 2019 that evaluated the benefits and harms of screening and antiviral therapy for preventing intermediate outcomes or health outcomes and the association between improvements in intermediate outcomes and health outcomes. New key questions focused on the yield of alternative HBV screening strategies and the accuracy of tools to identify persons at increased risk. Accuracy of Screening Tests and Risk Assessment The USPSTF previously reviewed the evidence on screening for HBV using serologic testing with HBsAg and found it to be accurate (both sensitivity and specificity were >98%).32 The current review found no studies that assessed the accuracy of tools for identifying persons at increased risk for HBV infection. Benefits of Early Detection and Treatment There are currently no randomized clinical trials comparing screening with no screening to provide direct evidence of the benefit of screening.11,19 Screening Strategies Evidence on screening strategies for identifying persons with HBV infection was limited to 3 fair-quality, retrospective studies in private primary care practices in Germany (n = 20,917), a French sexually transmitted infection clinic (n = 6194), and French clinics that served populations with high HBV prevalence (n = 3929). These studies found that screening based on broad criteria (immigration from countries with a high prevalence, other demographic risk factors, or behavioral risk factors) identified nearly all cases of HBV infection, with numbers needed to screen ranging from 32 to 148. Restricting screening to immigrants from high-prevalence (≥2%) countries was more efficient (numbers needed to screen ranging from 19 to 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 German primary care practices. The applicability of these studies to US primary care settings may be limited.11,19 Benefits of Treatment on Intermediate Outcomes Eighteen fair-quality trials (total N = 2972; n = 24-526; follow-up, 1.8-86 months) of antiviral therapy reported intermediate outcomes (eg, virologic suppression, normalization of alanine aminotransferase [ALT] levels, histologic improvement, and HBsAg loss or seroconversion) in persons aged 24 to 46 years. Six studies were conducted in the US or Europe. Trials evaluated first-line therapies (ie, therapies with the highest proven efficacy and safety, including nonpegylated interferon and entecavir) and alternate therapies (lamivudine and adefovir).11,19 Pooled analysis showed that antiviral therapy was statistically significantly more effective than placebo or no treatment in achieving histologic improvement, loss of HBsAg, loss of hepatitis B e-antigen (HBeAg), HBeAg seroconversion, virologic suppression, and normalization of ALT levels.11,19 Although there were some differences in the magnitude of the effect when trials were stratified by geographic region, antiviral therapy was consistently associated with increased likelihood of virologic suppression across regions. Stronger effects were also seen in studies with less than 1 year of follow-up than in studies with longer follow-up.11,19 Twelve good- or fair-quality trials (N = 4127; n = 44-715; duration, 3.7-22 months) in adults compared first-line vs alternate regimens, specifically entecavir vs lamivudine (6 studies), entecavir vs telbivudine (2 studies), pegylated interferon vs lamivudine (1 study), or tenofovir disoproxil fumarate (TDF) vs adefovir (3 studies). In 1 trial of pegylated interferon and in pooled analysis of 6 trials of entecavir, both first-line regimens achieved significantly higher virologic suppression or ALT normalization compared with lamivudine.11,19 Benefits of Treatment on Health Outcomes Seven fair-quality randomized trials (N = 1042; n = 42-356; duration, 12-86 months) compared the effects of antiviral therapy vs placebo or no treatment on cirrhosis, hepatocellular carcinoma, or mortality in adults. Three trials were conducted in the US or Europe; the remainder were conducted in Asia or multiple countries with varied HBsAg prevalence. Four trials assessed various interferon alfa regimens; 4 assessed lamivudine. Pooled analysis revealed that treatment was associated with significant reduction in mortality (3 trials; relative risk [RR], 0.15 [95% CI, 0.03-0.69]) and lower risk of incident cirrhosis (2 trials; RR, 0.72 [95% CI, 0.29-1.77]) or hepatocellular carcinoma (4 trials; RR, 0.60 [95% CI, 0.16-2.33]) that were not statistically significant. None of the trials evaluated effects of antiviral therapy in adolescents or how effects varied by age, race/ethnicity, or sex.11,19 Seven fair-quality cohort studies (N = 50,912; n = 632-43 190; duration, 2.7-8.9 years) compared antiviral therapy with no antiviral therapy in adults in the US (2 trials) or Asia (5 trials). Most studies adjusted for patient age, sex, and stage of fibrosis; some also adjusted for level of HBV DNA, ALT levels, or medical comorbid conditions. The trials assessed lamivudine (1 trial), entecavir (1 trial), or various regimens (5 trials). All studies found that antiviral therapy was associated with a decreased risk of hepatocellular carcinoma (adjusted hazard ratios [HRs] ranged from 0.24 to 0.64), including 2 US studies with median follow-up of 5.2 years (adjusted HR, 0.39 [95% CI, 0.27-0.56]) or 8.9 years (adjusted HR, 0.24 [95% CI, 0.15-0.39]).11,19 Association Between Intermediate Outcomes and Health Outcomes Nine fair-quality cohort studies (N = 3893; n = 63-1531; duration, 3.2-9.9 years) assessed the association between intermediate outcomes after treatment and health outcomes in adults in the US or Europe (6 trials) or Asia (3 trials) with varied baseline characteristics (eg, HBeAg status, presence of cirrhosis). The trials assessed interferon (6 trials), entecavir (2 trials), or lamivudine (1 trial). HBeAg loss or seroconversion was associated with a lower risk of cirrhosis (1 trial; adjusted HR, 0.41 [95% CI, 0.32-0.88]), hepatocellular carcinoma (1 trial; adjusted HR, 0.13 [95% CI, 0.08-0.57]), or a composite health outcome (1 trial; adjusted HR, 0.06 [95% CI, 0.01-0.61]). Other studies found associations between virologic suppression, ALT normalization, histologic improvement, or composite intermediate outcomes and a lower risk of hepatocellular carcinoma or composite health outcomes, but several associations were not statistically significant.11,19 Harms of Early Detection and Treatment No randomized clinical trials comparing HBV screening with no screening currently exist to provide direct evidence of the harms of screening.11,19 Twelve trials (N = 2106) reported on harms of treatment compared with no treatment or placebo. Pooled analyses found no significant differences in the risk of serious adverse events (4 trials; RR, 0.92 [95% CI, 0.45-1.85]), any adverse event (5 trials; RR, 1.01 [95% CI, 0.90-1.11]), renal adverse events (3 trials; RR, 1.27 [95% CI, 0.31-3.55]), or study withdrawal due to adverse events (3 trials; RR, 4.44 [95% CI, 0.95-20.77]). Nine trials (N = 3408) compared harms of first-line antiviral regimens with harms of alternate regimens. Pegylated interferon was associated with an increased risk of any adverse event compared with lamivudine in 1 trial (N = 543; RR, 1.58 [95% CI, 1.41-1.78]). No significant differences in risk of serious adverse events or withdrawal due to adverse events were found in trials that compared entecavir with lamivudine or compared TDF with adefovir. One fair-quality cohort study of Asian patients in the US (n = 1224) that compared risk of incident osteopenia or osteoporosis in patients treated with TDF or entecavir with patients receiving no therapy found no significant differences in these outcomes.11,19 Response to Public Comments A draft version of this recommendation statement was posted for public comment on the USPSTF website from May 5, 2020, through June 1, 2020. Respondents expressed concern that various high-risk populations were not discussed, requested additional information on follow-up testing, and expressed concerns about implementation. In the Additional Tools and Resources section, the USPSTF provides links to additional risk factors, lists tools and resources to help clinicians assess HBV risk, and discusses hepatitis B serologic tests in detail. The USPSTF addresses persons with combinations of risk factors and screening intervals in the Practice Considerations section.Research Needs and GapsThe USPSTF identified important gaps related to HBV screening and recommends research on the following. Development and validation of clinical decision support tools to help clinicians efficiently and accurately identify adolescents and adults at increased risk for HBV infection. Investigating alternative screening strategies defined by a person’s country of origin or other health or behavioral factors in the US. Development of rapid, point-of-care HBsAg tests for use in the US to facilitate screening and linkage to care for patients at risk for loss to follow-up. Additional trials with adequate duration and statistical power to evaluate the association between current first-line therapies (including recently approved tenofovir alafenamide) on long-term health outcomes of cirrhosis, end-stage liver disease, disease-specific and all-cause mortality, and quality of life and risk of HBV transmission. In the absence of randomized clinical trials, the development of registries that monitor treatment efficacy could be informative. Recommendations of OthersSeveral organizations have issued recommendations about screening nonpregnant adolescents and adults. The CDC, the American College of Physicians, and the American Association for the Study of Liver Diseases recommend screening for HBV infection in asymptomatic, high-risk persons, including all persons born in countries with an HBsAg prevalence of 2% or greater regardless of vaccination history; US-born persons not vaccinated as infants whose parents were born in regions with an HBsAg prevalence of 8% or greater; persons who inject drugs; men who have sex with men; and persons with HIV infection, persons with hepatitis C virus infection, inmates of correctional facilities, and household contacts and sexual partners of HBsAg-positive persons.2,4,21,33 Both the CDC and the American Association for the Study of Liver Diseases also recommend screening patients with conditions requiring immunosuppressive therapy, predialysis, hemodialysis, peritoneal dialysis, or home dialysis; patients who have elevated ALT levels of unknown etiology; or developmentally disabled persons and staff in residential facilities.2,4,21 The American Association for the Study of Liver Diseases also recommends screening persons with multiple sexual partners or a history of sexually transmitted infections.21 The American Academy of Family Physicians34 endorses the 2014 USPSTF recommendation on HBV screening.


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