Screening At-Risk Individuals for Hepatitis B: What Do the Guidelines Say?

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http://www.medscape.com/viewarticle/583707

Selection from: Hepatitis B: Advances in Screening, Diagnosis, and Clinical

Management - Volume 4

Screening At-Risk Individuals for Hepatitis B: What Do the Guidelines Say? CME

T. Frenette, MD G. Gish, MD

Disclosures

Introduction

Hepatitis B remains a serious global health problem. Infection with the

hepatitis B virus (HBV) is a leading cause of mortality worldwide, and is

associated with an increased risk for liver failure, cirrhosis, and

hepatocellular carcinoma. Indeed, 350-400 million persons have chronic hepatitis

B, with 1.5-2 million infected individuals residing in the United States.[1-3]

The HBV vaccine is effective in preventing hepatitis B and its consequent liver

disease, and improved identification and vaccination of at-risk individuals can

prevent serious sequelae of infection.[4,5] Persons with chronic hepatitis B can

remain asymptomatic for years; have normal liver tests; and be unaware of their

infection, of the risks for transmission to others, and of the risk for serious

disease later in life. Screening is recommended for select populations, with

subsequent follow-up for infected individuals, and vaccination as appropriate

for those not infected or immune.[6-8]

Transmission and Clinical Features

HBV is transmitted via exposure to blood or mucous membranes with infectious

bodily fluids. In children, the primary mode of transmission is vertically at

birth, or through iatrogenic events; folk remedies, such as acupuncture,

vacuuming, and coin rubbing; or exposure to infected bodily fluids via

person-to-person contact. In adults, the primary mode of transmission is via

sexual exposure or percutaneous/mucosal exposure to infectious blood/bodily

fluids (horizontal transmission), such as through needle sharing in injection

drug users or exposure to infected blood or needles in the healthcare

setting.[6] Other potential sources of transmission include direct percutaneous

exposure of susceptible individuals to virus during blood transfusion or organ

transplant.[6] Person-to-person transmission of HBV can also occur in settings

involving close interpersonal contact over an extended period of time, such as

in household contacts or developmentally disabled persons living in long-term

care facilities.[7]

Clinical manifestations of acute infection rarely occur in infants and children.

Nonimmunosuppressed adults more commonly have symptomatic disease, and the

presence of symptoms in immunosuppressed adults is highly variable.[9]

Individuals with defective immune responses, such as dialysis patients, may not

have symptoms with acute infection, whereas those with HIV infection or

recipients of organ transplant may have severe or fulminant hepatitis. When

clinical manifestations of acute disease occur, illness typically begins 2-3

months after exposure to the virus. Symptoms of acute HBV infection include

fatigue, loss of appetite, nausea, arthralgias, vomiting, abdominal pain,

low-grade fever, jaundice, dark urine, and light-colored stools.

The acute illness generally lasts 2-4 months. Acute hepatitis B becomes chronic

in> 90% of infants, in 25% to 50% of children aged 1-5 years, and in < 5% of

older children and adults.[8,9] Patients who are immunosuppressed, including

those infected with HIV or on hemodialysis, are at increased risk of developing

chronic infection.[10] Once chronic infection occurs, 0.5% of infected patients

who acquire disease early in life spontaneously resolve the infection annually

(as determined by undetectable hepatitis B surface antigen [HBsAg] and HBV DNA

and normalization of serum alanine aminotransferase [ALT]). In patients with

adult-acquired disease, the rate of spontaneous seroclearance of HBV can be

approximately 1% per year or higher depending on the genotype (genotype A) or

the level of immune activation (the degree of elevation in serum ALT).[8,11] Of

those patients who develop chronic HBV infection as children, 25% will die from

the consequences of hepatitis B, such as cirrhosis or liver cancer.[8] Most

patients remain asymptomatic until the onset of end-stage liver disease.

Screening for HBV: Rationale

Screening is a basic public health tool that is used to identify unrecognized

health conditions prior to symptom onset, such that treatment can be offered and

appropriate interventions implemented to prevent continued transmission.

Screening depends on the ability to reach at-risk populations, and needs to be

easy and acceptable. In addition, identification of persons with disease needs

to enable healthcare providers to address the issues in order to reduce future

disease burden and, in the case of communicable diseases, to reduce

transmission. Screening for chronic HBV infection is consistent with the

accepted public health screening criteria in that it allows for diagnosis before

symptoms occur by using a test that is accurate, reliable, and minimally

invasive, permitting interventions that can result in years of life gained, with

the costs of screening reasonable relative to the potential benefits.[12]

Currently, screening for hepatitis B is recommended by all major liver disease

organizations and by the US Centers for Disease Control and Prevention

(CDC).[6-8]

Screening for Hepatitis B: Serologic Tests

Persons who are at risk for hepatitis B should be screened for HBsAg, hepatitis

B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc).[7,13]

Anti-HBc total (both immunoglobulin [ig]G and IgM) should be measured when

screening for chronic hepatitis B, and anti-HBc IgM, which defines acute

infection or viral reactivation, should be tested when acute infection is

suspected.[6] Anti-HBc indicates exposure to HBV infection and can be positive

in either the chronic carrier state or in patients with resolved infection. In

patients with isolated anti-HBc, one third are considered to be false-positive

and two thirds are considered to be very low-level carriers who are at risk for

reactivation if the individual is treated with immunosuppressive medications.

Further interpretation of these tests is summarized in the Table. These

screening tests will identify patients who are chronically infected, patients

who require vaccination, and patients who have been exposed in the past and

cleared the virus.

Table. Interpretation of Serologic Test Results for Hepatitis B

Serologic Marker Interpretation

HBsAg Total HBcAb IgM HBcAb HBsAb

- - - - Never infected

+ - - - Early acute infection; transient (up to 18 days) after vaccination

+ + + - Acute infection

- + + + or - Acute resolving infection

- + - + Recovered from past infection and immune

+ + - - Chronic infection

- + - - Past infection; false positive (ie, susceptible); occult infection; or

passive transfer of HBcAb to infant born to HBsAg-positive mother

- - - + Immune if concentration is> 10 mIU/mL after vaccination series complete;

passive transfer after hepatitis B immune globulin administration

HBsAg = hepatitis B surface antigen; total HBcAb = total hepatitis B core

antibody; IgM HBcAb = immunoglobulin M hepatitis B core antibody; HBsAb =

hepatitis B surface antibody; + = positive test result; - = negative test result

HBsAg positivity is associated with acute or chronic infection. If HBsAg is

present for longer than 6 months, it is consistent with transition to chronic

infection. Patients who are HBsAg-positive should be further screened by testing

for serum HBV DNA, hepatitis B e antigen (HBeAg), and hepatitis B e antibody

(anti-HBe) to fully characterize the status of the hepatitis B infection and

help guide recommendations in regard to antiviral treatment. HBeAg positivity is

associated with more active disease. Testing should also be done to rule out

concomitant infection with hepatitis delta virus (HDV; test for anti-HDV

antibodies and HDV antigen).[8,14] All HBsAg-positive patients should be

considered infectious, and should be counseled in regard to transmission of

disease. They should also undergo liver enzyme and function testing as well as

testing for immunity to hepatitis A with vaccination as needed, and ultrasound

examination of the liver, with discussion in regard to the benefits of liver

biopsy.[8,15]

In persons who have acute HBV infection, HBsAg is the only serologic marker

detected during the first 3-5 weeks.[13] Anti-HBc appears at the onset of

symptoms or liver test abnormalities in the setting of acute HBV infection, and

persists for life in most patients, first as IgM and later as IgG. The presence

of the IgM class of anti-HBc can help distinguish between recently acquired

infection and chronic infection, although it can occasionally reappear during an

acute flare of chronic hepatitis B.[16] In individuals who recover from

hepatitis B, HBsAg generally clears from the serum, and anti-HBs appears,

typically within 3-4 months of exposure.[13] HBsAg clearance and development of

anti-HBs rarely occur in patients with chronic infection.

The presence of anti-HB without HBsAg indicates immunity to hepatitis B;

anti-HBs also appears after vaccination. In persons who become chronically

infected, HBsAg and anti-HBc persist.

Patients may also have isolated total anti-HBc positivity. In patients with no

risk factors and in populations with low prevalence of disease, this finding can

be a false-positive test. In patients with risk factors for HBV infection or

from areas of high prevalence, isolated anti-HBc positivity generally indicates

prior exposure to hepatitis B, with waning of anti-HBs levels.[16] Anti-HBs will

return after vaccination. Occasionally, occult HBV infection can be present --

HBV DNA in the absence of HBsAg. Patients who are HIV-positive or

immunosuppressed should be considered for testing for HBV DNA in the presence of

isolated anti-HBc positivity.[17]

Who Should Be Screened?

To prevent the transmission of HBV infection, guidelines have recommended HBV

screening for hemodialysis patients, pregnant women, and persons with known or

suspected exposure to hepatitis B (ie, during an outbreak, infants born to

HBV-infected mothers, household contacts and sexual partners of HBV-infected

persons, inmates at correctional facilities, and individuals with occupational

or other exposures to infectious blood or body fluids -- including hepatitis C

virus [HCV]-infected individuals).[6-8,18] Testing is also required for blood,

organ, and tissue donors. Testing is recommended for HIV-infected patients

because of the high prevalence of HBV coinfection and the increased risk for

hepatitis B-associated morbidity and mortality; it is also recommended for the

following additional special populations: persons from regions of high

prevalence, men who have sex with men, injection drug users, persons with

elevated serum ALT of unknown etiology, and candidates for immunosuppressive

therapies.[7,8]

HIV-Infected Patients

HBV and HIV have similar transmission patterns; thus, all HIV-positive patients

should undergo screening for HBV.[7,8,19-21] The prevalence of HBV coinfection

in HIV-infected patients is estimated to be 8%.[19-21] In cases of isolated

anti-HBc positivity, serum HBV-DNA should be tested to evaluate for occult HBV

infection, which can occur in 1% to 12% of patients who have this serologic

profile.[19] HIV antiviral medications often have cross-reactivity against HBV,

so screening should be done to reduce the risk for HBV antiviral resistance in

this population.

Regions of High Prevalence

In the United States, the Asian/Pacific Islander community, which accounts for

much of the high-prevalence population, is rapidly growing, and is expected to

reach about 8% of the US population by 2050, with chronic hepatitis B present in

2% to 20% of all persons.[22,23] Since the early 1990s, expert guidelines have

recommended screening for hepatitis B in patients born in regions with an HBV

prevalence> 8%.[4,5] These regions include Asia, the Pacific Islands, Africa,

the Middle East, and parts of Eastern Europe. Recent guidelines published by the

CDC have expanded these recommendations to include anyone born in geographic

regions in which the prevalence of HBsAg ™ 2% (Figure).[7] This testing should

be performed regardless of vaccination status in the person's country of origin,

as often persons are vaccinated without prior HBV testing. In addition, persons

born to parents who were born in regions with high HBV prevalence (> 8%) should

also be screened for hepatitis B if they were not vaccinated as infants in the

United States. Transmission of hepatitis B from mother to infant is nearly

universal, and results in chronic infection in> 90% of cases.[9]

Figure. Geographic distribution of chronic hepatitis B virus (HBV) infection --

worldwide, 2006.*

(Click to enlarge)

Persons With Behavioral Exposure to HBV

Past or present injection drug users have a higher prevalence of chronic HBV

infection than the general population, and thus are now recommended to undergo

screening for HBV, followed by routine vaccination if testing is negative.[7,8]

Current data suggest that after 1 year of injection drug use, 9% of users are

infected with HBV, and after 10 years of use, 41% of users are infected.[24,25]

It is recommended that all injection drug users undergo serologic testing, and

that the first dose of hepatitis B vaccine be administered during the same

medical visit as the serologic testing.[7,26,27] If testing is not feasible,

however, vaccination of the injection drug user should still continue without

prior screening with the goal of preventing transmission.

Men who have sex with men also comprise a population with a higher prevalence of

HBV infection than the general population, as well as have an ongoing risk for

infection; they currently account for 15% of all cases of acute HBV

infections.[6] Updated guidelines now recommend that this population undergo

screening and subsequent vaccination for HBV.[7]

Patients With Elevated Serum ALT of Unknown Etiology

Over 50% of patients with acute hepatitis B have no identifiable risk factor for

transmission; about as many patients with chronic hepatitis B are unaware of

their infection.[6,23] Given that hepatitis B can be asymptomatic, the updated

CDC guidelines now recommend that all patients with elevated ALT levels of

unknown etiology undergo screening for hepatitis B.[7] The definition of

elevated serum ALT should take into account " normal " vs " healthy " levels. Many

times it is likely that the upper limit of normal for serum ALT is overestimated

because of the use of populations that include patients with subclinical liver

disease for the determination of normal reference ranges.[15] A large

retrospective study of first-time blood donors found that the upper limit of

normal for serum ALT was significantly lower than the previously established

limits.[28] Thus, the upper limit of normal for ALT levels should be considered

30 IU/L for men and 19 IU/L for women.[15] Indeed, 1% to 6% of patients with

increased serum ALT ultimately test positive for hepatitis B, making this a

worthwhile population to screen.[27]

Patients Receiving Cytotoxic or Immunosuppressive Therapy

Patients who are HBsAg-positive can reactivate HBV infection and develop acute

flares of disease if they undergo treatment that results in immune

suppression.[29] Thus, the updated CDC guidelines recommend that persons

receiving cytotoxic or immunosuppressive therapy -- chemotherapy,

immunosuppression related to organ transplantation, or immunosuppression for

rheumatologic or gastroenterologic disorders -- should be screened for hepatitis

B and receive prophylactic antiviral therapy during and for 6 months after

cytotoxic or immunosuppressive treatment, to prevent reactivation of

disease.[7,8]

Pregnant Women

For a newborn infant whose mother is positive for both HBsAg and HBeAg, the risk

for chronic hepatitis B infection ranges from 70% to 90% by age 6 months in the

absence of postexposure immunoprophylaxis.[4] If the mother is HBsAg-positive,

but HBeAg-negative, the risk for chronic infection is much less, on the order of

10%.[4] Because of this risk, all pregnant women are advised to undergo

screening for HBV infection with serologic testing for HBsAg during an early

prenatal visit, even if they have been previously vaccinated or tested.[4,7,8]

All women who engage in high-risk behaviors (ie, injection drug use, sexual

partner of HBsAg-positive person, multiple sexual partners in the prior 6

months, or history of sexually transmitted disease) should undergo repeat

testing for HBsAg at the time of admission to the hospital for delivery.[4]

HBsAg-positive pregnant women should be advised of the need for their infants to

receive hepatitis B vaccination and hepatitis B immune globulin.[7] All infants

born to HBsAg-positive mothers should receive hepatitis B immune globulin at

birth, as well as the first dose of hepatitis B vaccine. In these infants,

postvaccination testing for HBsAg and anti-HBs should be performed after

completion of the vaccine series, at age 9-18 months, but not prior to 9 months

to avoid detection of passive acquisition of anti-HBs from hepatitis B immune

globulin administration.[4]

Patient Education

Once a person screens/tests positive for HBsAg, he/she should be counseled on

strategies to avoid transmission and in regard to treatment options to reduce

the chance of further liver damage. HBsAg-positive patients should be advised to

notify their household and sexual contacts that they should be tested and

vaccinated as appropriate, and to use methods to prevent transmission.[7] Condom

use during sexual activity is advised if their partner does not have documented

immunity to hepatitis B. Patients should cover cuts and skin lesions to prevent

spread of virus, and all blood spills should be cleaned with a bleach solution.

In addition, HBsAg-positive individuals should be advised to avoid sharing

personal items, such as razors or toothbrushes, that could be contaminated with

blood.

Patients should be advised to limit or stop alcohol consumption due to its

effects on the liver, and to be vaccinated against hepatitis A. In addition,

patients who have tested positive for HBsAg should undergo testing for serum HBV

DNA, HBeAg, and anti-HBe. They should seek follow-up with a provider experienced

in the management of hepatitis B to determine whether ultrasound, liver biopsy,

hepatocellular carcinoma screening, or antiviral therapy is warranted.

At present, 7 agents are approved by the US Food and Drug Administration for the

treatment of chronic hepatitis B: interferon alfa-2b; pegylated interferon

alfa-2a; and the oral antivirals, lamivudine, adefovir dipivoxil, entecavir,

telbivudine, and tenofovir disoproxil fumarate. With the therapeutic landscape

for hepatitis B continuing to evolve, several other agents, including clevudine

and emtricitabine, are undergoing phase 3 trials for chronic hepatitis B.

If a patient screens negative for hepatitis B, he/she should complete the HBV

vaccine series. HBV vaccination has been found to be safe, and is effective in>

90% of patients if all 3 doses of the vaccine are administered.[4,5]

Multiple healthcare providers play an important role in screening persons for

hepatitis B infection, and should continually seek ways to improve screening.

Currently, medical compliance with screening recommendations is excellent in

certain populations, but lower in other settings.[7] For example, 99% of

pregnant women deliver their infants in hospitals, and 89% to 96% of them are

tested for HBV infection. Susceptible dialysis patients are tested monthly in

most centers. Unfortunately, compliance needs to be improved in other important

areas. In primary care offices, for example, only 30% to 50% of persons born in

regions of high hepatitis B prevalence were screened.[7,30] Barriers to testing

occur on multiple levels, including at the level of patients, providers, and

resources. Surveys of primary care physicians have revealed that although many

believe that testing is important, they often do not follow through.[31,32]

Possible reasons include reluctance to ask about risk factors, miscommunication

due to language barriers, or lack of knowledge of treatment options. Patients

may be reluctant to be tested due to lack of knowledge, fear of ostracism, or

family barriers. Lack of resources is another major problem to effective

implementation of screening programs, with many patients who are at risk for

hepatitis B being uninsured or underinsured. Thus, the development of

partnerships between health departments and community organizations may help

with community outreach and overall education to encourage individuals to be

tested for HBV. These alliances may have particular utility in addressing

potential social and cultural barriers to screening/testing and medical care,

whereas providers whose patients may comprise high-prevalence areas or who treat

HBV-infected patients along with professional medical organizations can help

guide/improve HBV screening efforts.

Conclusion

Although the prevalence of acute hepatitis B in the United States is decreasing,

it remains an important public health issue, with 1.5-2 million persons

currently infected and a lifetime mortality rate of 7% to 30%.[33] The

availability of a hepatitis B vaccine has markedly reduced the number of acute

cases of HBV infection, especially in children and adolescents, but there

continues to be a substantial incidence of new infections in injection drug

users and persons with high-risk sexual behavior, and there continues to be

newly diagnosed disease in immigrants. Perinatal transmission has been

significantly decreased with the implementation of universal infant vaccination,

and transfusion/iatrogenic infection has been nearly eradicated by screening

blood products and vaccination of medical professionals at risk. The CDC and

other experts continue to expand recommendations for populations to screen for

hepatitis B, and healthcare providers need to make screening and vaccination a

priority in order to continue to reduce the prevalence of HBV infection and

HBV-related chronic liver disease.

This activity is supported by an independent educational grant from Gilead

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References