Hepatitis B: Screening, Prevention, Diagnosis, and Treatment

Thad Wilkins; Richard Sams; Mary Carpenter

THAD WILKINS, MD, MBA, RICHARD SAMS, MD, MA, AND MARY CARPENTER, PharmD

Am Fam Physician. 2019;99(5):314-323

See related AFP Community Blog post: Family Doctors Can Easily Treat Hepatitis B "In-House"

Patient information: See related handout on hepatitis B, written by the authors of this article.

Author disclosure: No relevant financial affiliations.

Hepatitis B virus (HBV) is a partly double-stranded DNA virus that causes acute and chronic liver infection. Screening for hepatitis B is recommended in pregnant women at their first prenatal visit and in adolescents and adults at high risk of chronic infection. Hepatitis B vaccination is recommended for medically stable infants weighing 2,000 g or more within 24 hours of birth, unvaccinated infants and children, and unvaccinated adults requesting protection from hepatitis B or who are at increased risk of infection. Acute hepatitis B is defined as the discrete onset of symptoms, the presence of jaundice or elevated serum alanine transaminase levels, and test results showing hepatitis B surface antigen and hepatitis B core antigen. There is no evidence that antiviral treatment is effective for acute hepatitis B. Chronic hepatitis B is defined as the persistence of hepatitis B surface antigen for more than six months. Individuals with chronic hepatitis B are at risk of hepatocellular carcinoma and cirrhosis, but morbidity and mortality are reduced with adequate treatment. Determining the stage of liver disease (e.g., evidence of inflammation, fibrosis) is important to guide therapeutic decisions and the need for surveillance for hepatocellular carcinoma. Treatment should be individualized based on clinical and laboratory characteristics and the risks of developing cirrhosis and hepatocellular carcinoma. Immunologic cure, defined as the loss of hepatitis B surface antigen with sustained HBV DNA suppression, is attainable with current drug therapies that suppress HBV DNA replication and improve liver inflammation and fibrosis. Pegylated interferon alfa-2a, entecavir, and tenofovir are recommended as first-line treatment options for chronic hepatitis B.

The Centers for Disease Control and Prevention (CDC) estimated that in 2015 there were 21,900 cases of acute hepatitis B, with an overall incidence of 1.1 cases per 100,000.¹ There are an estimated 850,000 to 2.2 million individuals in the United States with chronic hepatitis B.^1,2 Approximately 25% of children and 15% of adults with chronic hepatitis B die prematurely from hepatocellular carcinoma (HCC) or cirrhosis.³ However, treatment reduces morbidity and mortality from the disease.

WHAT IS NEW ON THIS TOPIC

Approximately 1,000 cases of perinatal hepatitis B occur annually in the United States, and nearly 90% of chronic hepatitis B cases in infants develop in the first year of life.

Hepatitis B vaccination is recommended for all medically stable infants weighing 2,000 g (4 lb, 6 oz) or more within 24 hours of birth, unvaccinated infants and children, and unvaccinated adults requesting protection from hepatitis B or who are at increased risk of hepatitis B.

Clinical recommendation	Evidence rating	References
Pregnant women should be screened for hepatitis B at the first prenatal visit.	A	6
Adolescents and adults at high risk of chronic infection should be screened for hepatitis B.	B	7
Hepatitis B vaccination is recommended for all medically stable infants weighing 2,000 g (4 lb, 6 oz) or more within 24 hours of birth, unvaccinated infants and children, and unvaccinated adults requesting protection from hepatitis B or who are at increased risk.	C	11
Acute hepatitis B should not be treated with antivirals.	B	17
All infants born to mothers who are positive for hepatitis B surface antigen should receive hepatitis B immune globulin promptly and the hepatitis B vaccine by 24 hours of life.	C	25
Pegylated interferon alfa-2a (Pegasys), entecavir (Baraclude), and tenofovir are recommended as first-line treatment options for chronic hepatitis B.	C	27

The hepatitis B virus (HBV) is a DNA virus that is unusual in that its genome is only partly double stranded. The host cell DNA polymerases repair the DNA into a covalently closed circular DNA.⁴ The accumulation of covalently closed circular DNA in the nucleus of the hepatocyte is the basis for the persistence of HBV despite antiviral therapy⁵ (eFigure A). The HBV has 10 genotypes (A through J) and more than 30 subtypes.⁴

Screening and Prevention

The U.S. Preventive Services Task Force and American Academy of Family Physicians recommend screening for hepatitis B in pregnant women at the first prenatal visit and in adolescents and adults at high risk of chronic infection.^6–8 In addition to other risk factors, the CDC uses a regional prevalence threshold of 2% or greater to define high risk.⁹ Table 1 includes indications for screening.^7,9 Screening for hepatitis B includes testing for hepatitis B surface antigen (HBsAg) and, if positive, testing for antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc) to distinguish between infection and immunity ^7,10 (Table 2¹¹).

HBsAg*	Total anti-HBc†	IgM anti-HBc	Anti-HBs‡	HBV DNA	Interpretation
−	−	−	−	−	Never infected
+	−	−	−	+ or −	Early acute infection; transient (up to 18 days) after vaccination
+	+	+	−	+	Acute infection
−	+	+	+ or −	+ or −	Acute resolving infection
−	+	−	+	−	Recovered from past infection; immune
+	+	−	−	+	Chronic infection
−	+	−	−	+ or −	False-positive result
−	−	−	+	−	Immune if anti-HBs concentration is ≥ 10 mIU per mL after completion of vaccine series; passive transfer after administration of hepatitis B immune globulin

IMMUNIZATION

The Advisory Committee on Immunization Practices recommends hepatitis B vaccination for all medically stable infants weighing 2,000 g (4 lb, 6 oz) or more within 24 hours of birth, unvaccinated infants and children, and unvaccinated adults requesting protection from hepatitis B or who are at increased risk of infection.¹¹ There are several hepatitis B vaccines available, including the new two-dose vaccine, Heplisav-B.^12,13

Postvaccination testing is recommended only in individuals who may not elicit a complete response to the vaccine based on risk factor assessment. In certain populations (i.e., persons on hemodialysis; persons who are immunocompromised, such as those with HIV infection; sex partners of persons positive for HBsAg; and health care personnel), testing for anti-HBs should be performed one to two months following the completion of the vaccine series.^14,15 A responder is defined as a person with an anti-HBs level of 10 mIU per mL or more after completion of the vaccine series.³ If the anti-HBs level is less than 10 mIU per mL after the initial vaccine series, revaccination is indicated.¹⁵

Revaccination can be completed using one of two approaches: (1) administration of a second complete hepatitis B vaccine series followed by anti-HBs testing one to two months later, or (2) administration of a single dose of hepatitis B vaccine followed by anti-HBs testing one to two months later. If the anti-HBs level remains less than 10 mIU per mL after a single dose, completion of the series should be performed with anti-HBs testing one to two months after completing the series.¹² A nonresponder is defined as a person with an anti-HBs level of less than 10 mIU per mL after six doses or more of the hepatitis B vaccine.³

The CDC does not recommend administration of more than two complete hepatitis B vaccine series, except for patients on hemodialysis, in whom anti-HBs testing should be conducted annually and a booster dose of the vaccine administered when the anti-HBs level declines to less than 10 mIU per mL.^15,16

Diagnosis

ACUTE HEPATITIS B

Acute hepatitis B is defined as the discrete onset of symptoms (e.g., fever, headache, malaise, anorexia, nausea, vomiting, diarrhea, abdominal pain), the presence of jaundice or elevated serum alanine transaminase (ALT) levels, and test results showing HBsAg and HBcAg.¹ A Cochrane review of seven randomized controlled trials with 597 participants found that antiviral treatment has no benefit for acute hepatitis B based on low-quality or very low-quality evidence.¹⁷ An individual with acute hepatitis B may achieve complete immune clearance yielding lifelong immunity or develop chronic hepatitis B. The younger the age at the time of infection, the higher the probability of developing chronic infection.¹⁸

Hepatitis B e antigen (HBeAg) may be detected in the serum of individuals with early acute hepatitis B, soon after HBsAg becomes detectable. The presence of HBeAg in the serum correlates with high levels of infectivity. During recovery from acute hepatitis B, HBeAg becomes undetectable in the serum, while antibodies to HBeAg (anti-HBe) become detectable. Anti-HBe usually remain detectable for years after recovery.

CHRONIC HEPATITIS B

Chronic hepatitis B, defined as the persistence of HBsAg for more than six months, has five distinct phases¹⁹ (Table 3²⁰). The initial evaluation of individuals with chronic hepatitis B includes a complete history and examination. There should be a special emphasis on signs and symptoms of cirrhosis, evaluation of alcohol intake and metabolic risk factors, family history of HCC, and hepatitis A and B vaccination status.²

Phase	Old terminology	HBsAg	HBeAg	HBV DNA	ALT	Liver inflammation	Comments
1	Immune tolerant	+++	+	++	Normal	None or minimal	Highly infectious because of high levels of HBV DNA
2	Immune reactive HBeAg positive	++	+	+	Elevated	Moderate to severe	Outcome of this phase is variable
3	Inactive carrier	+	−	Undetectable or +	Normal	None	Low risk of progression to cirrhosis or hepatocellular carcinoma, if the patient remains in this phase
4	HBeAg negative	−	−	++, persistent or fluctuating	Elevated	Moderate to severe	Usually with detectable antibodies to HBeAg; associated with low rates of spontaneous disease remission
5	Occult hepatitis B	−	−	Undetectable	Normal	Variable	Positive for antibodies to HBcAg, with or without detectable antibodies to HBsAg; HBV DNA (covalently closed circular DNA) are often detected in the liver

Laboratory measurements include a complete blood count with platelets, aspartate transaminase, ALT, total bilirubin, alkaline phosphatase, albumin, and international normalized ratio. Serology testing includes HBeAg, anti-HBe, HBV DNA quantitation or viral load, HBV genotype, and anti–hepatitis A virus to determine the need for vaccination.² Testing for coinfection with hepatitis C virus and HIV is recommended.²

The resolution of chronic hepatitis B is defined as the clearance of HBsAg with the detection of anti-HBs. Annually, approximately 0.5% of individuals with inactive chronic hepatitis B will have spontaneous clearance of HBsAg, and most will develop anti-HBs.² Among adults with untreated chronic hepatitis B, the cumulative five-year incidence of cirrhosis is 8% to 20%, and the risk of HCC is 2% to 5%.²

The risk of liver-related complications is variable and influenced by a variety of host, viral, and environmental factors.² Determining the stage of liver disease (e.g., evidence of inflammation, fibrosis) is important to guide therapeutic decisions and the need for HCC screening.² Although liver biopsy is recommended for assessing inflammatory activity and fibrosis, noninvasive tests, such as transient elastography or a serum fibrosis panel, are also useful.²

It is unclear which patients might benefit from screening for HCC. Some experts recommend screening patients with chronic hepatitis B only if they have other risk factors for HCC, whereas others advocate screening all individuals with chronic hepatitis B.

A Cochrane review of three randomized controlled trials found insufficient evidence to support or refute the value of alpha fetoprotein testing, ultrasound screening, or both.²¹ However, a randomized controlled trial of individuals with chronic hepatitis B found a 37% reduction in mortality for those who underwent surveillance vs. those who did not.²²

Chronic hepatitis B accounts for approximately one-half of all HCC cases.²³ Recent guidelines recommend screening for HCC every six months with abdominal ultrasonography and alpha fetoprotein testing.²⁴ If ultrasound findings are abnormal, then computed tomography or magnetic resonance imaging of the liver is recommended.²³ Treatment does not eliminate the risk of HCC; therefore, surveillance for HCC should continue.²

Postexposure Management

OCCUPATIONAL EXPOSURE

The CDC provides detailed guidance on the management of health care personnel potentially exposed to the HBV.³ All health care personnel should immediately report any blood or bodily fluid exposures to their occupational health offices. After exposure to blood or bodily fluids, the patient's hepatitis B vaccination status should be assessed to determine if he or she is a known responder to the vaccine based on an anti-HBs level of 10 mIU per mL or more. Informed consent should be obtained from the source person in accordance with state laws, and his or her blood should be obtained and tested for HBsAg. If it is not possible to test the source person's blood, the exposed patient should be managed as if the source person is positive for HBsAg.

Patients who are known responders to the hepatitis B vaccine require no further action. Management recommendations for health care personnel exposed to the HBV are summarized in Table 4.³

Status of patient	Postexposure test results		Postexposure prophylaxis		Postvaccination serologic testing needed?†

	Source person (HBsAg)	Patient (anti-HBs)	Hepatitis B immune globulin*	Vaccination
Documented responder: anti-HBs ≥ 10 mIU per mL after complete vaccine series (≥ three doses)	No action needed
Documented nonresponder: anti-HBs < 10 mIU per mL after ≥ six vaccine doses	Positive or unknown	Negative‡	Two doses separated by one month	None	No
	Negative	No action needed
Response unknown after three vaccine doses	Positive or unknown	< 10 mIU per mL‡	One dose	Initiate revaccination	Yes
	Negative	< 10 mIU per mL	None	Initiate revaccination	Yes
	Any result	≥ 10 mIU per mL	No action needed
Unvaccinated, incompletely vaccinated	Positive or unknown	Negative‡	One dose	Complete vaccination	Yes
Unvaccinated, incompletely vaccinated	Negative	Negative	None	Complete vaccination	Yes

PERINATAL EXPOSURE

Approximately 1,000 cases of perinatal hepatitis B occur annually in the United States, and nearly 90% of chronic hepatitis B in infants develops in the first year of life.²⁵ All infants born to mothers who are HBsAg positive should receive hepatitis B immune globulin promptly and the hepatitis B vaccine by 24 hours of life.²⁵ The vaccination series should be completed, and postvaccination serologic testing should be performed at nine to 12 months of age to assess response to vaccination. Additional vaccine doses should be administered if the infant is determined to be a nonresponder.²⁶

Treatment

GOALS OF THERAPY

Immunologic cure, defined as the loss of HBsAg with sustained HBV DNA suppression, is attainable with current drug therapies. However, because current treatments cannot eradicate the virus, including the covalently closed circular DNA, reactivation may occur.² Goals of therapy that correlate with improvements in patient-oriented outcomes include HBV DNA suppression, HBeAg loss/seroconversion (for individuals who were HBeAg positive), ALT normalization, and HBsAg loss.²

TREATMENT INDICATIONS

Serum ALT and HBV DNA levels and severity of liver disease are objective criteria used to assess the need for therapy.²⁷ Physicians should individualize treatment decisions based on clinical and laboratory characteristics and risks of developing cirrhosis and HCC.²⁷

Lifelong monitoring is required for individuals with chronic hepatitis B who are not currently candidates for treatment, because they may become candidates in the future.²⁷ For these patients, ALT levels should be monitored every three months during the first year and every six to 12 months thereafter. If ALT levels or aspartate transaminase levels become elevated, HBV DNA testing should be performed, and ALT levels should be monitored more often.²

Table 5 includes treatment recommendations for patients with chronic hepatitis B.²

HBV DNA	Alanine transaminase	Liver assessment	Recommendation
HBeAg negative
> 2,000 IU per mL	> 2 times ULN	Not required	Treatment indicated
> 2,000 IU per mL	> ULN, < 2 times ULN	Liver biopsy or noninvasive testing before treating	Immediate treatment not required; treat if biopsy shows moderate to severe inflammation or significant fibrosis
> 2,000 IU per mL	Normal	Not required	Monitor every three months
≤ 2,000 IU per mL	Normal	Not required	Monitor every three to six months
HBeAg positive
> 20,000 IU per mL	> 2 times ULN	Not required	Treatment indicated
> 20,000 IU per mL	> ULN, < 2 times ULN	Consider liver biopsy or noninvasive testing in individuals older than 40 years who have a family history of hepatocellular carcinoma or who have had previous treatment	Monitor every three to six months; treat if biopsy shows moderate to severe necroinflammation and/or moderate fibrosis
> 20,000 IU per mL	Normal	Not required	Monitor every six months; treat selected patients older than 40 years with HBV DNA level > 1,000,000 IU per mL and liver biopsy showing significant necroinflammation or fibrosis

TREATMENT OPTIONS

There are eight approved treatments for chronic hepatitis B in the United States.² These antiviral treatments fall into two classes: peginterferon alfa-2a agents and nucleoside/nucleotide analogues² (Table 6^2,28–36). Pegylated interferon alfa-2a (Pegasys), entecavir (Baraclude), and tenofovir are recommended as first-line treatment options.²⁷ There are two treatment approaches: a defined treatment period with a peginterferon alfa-2a or long-term treatment with a nucleoside/nucleotide analogue.

Drug and dosage*	Cautions and monitoring of treatment	Potential adverse effects and monitoring of treatment	Effect	Cost†
Pegylated interferon alfa-2a (Pegasys), interferon alfa-2b (Intron A) Adults (pegylated interferon alfa-2a): 180 mcg subcutaneously per week for 48 weeks Children one year or older (interferon alfa-2b): 3 million IU per m² subcutaneously three times per week, followed by 6 million IU per m² subcutaneously three times per week, for a total duration of 16 to 24 weeks (maximal dose: 10 million IU) Children three years and older (pegylated interferon alfa-2a): 180 mcg per 1.73 m² × body surface area once weekly for 48 weeks (maximal dose: 180 mcg)	May cause or exacerbate autoimmune, infectious, ischemic, thyroid, and neuropsychiatric disorders, and hemorrhagic cerebrovascular events Use caution in patients with uncontrolled seizure disorder, renal impairment, diabetes mellitus, or cardiovascular disease Monitoring: Complete blood count and chemistries, including liver function tests and uric acid level every one to three months, thyroid-stimulating hormone level every three months, and HBeAg, anti-HBe, serum HBV DNA levels every six months; clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications	Adults: Flulike symptoms, bone marrow suppression, headache, fatigue Children: Growth suppression (weight, height)	Pegylated interferon alfa-2a had 30% HBeAg seroconversion and HBV DNA suppression compared with placebo Pegylated interferon alfa-2a was superior to lamivudine in HBsAg clearance and seroconversion for patients who were HBeAg positive or negative Patients who were HBeAg negative had significantly higher response rates, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a compared with lamivudine	Adults: — ($4,200) Children: — ($1,830)
Oral antiviral agents (nucleoside/nucleotide analogues) Adefovir (Hepsera) Adults and children ≥ 12 years: 10 mg orally per day	Use caution in patients with renal impairment or individuals at risk of renal toxicity, including concurrent nephrotoxic agents or nonsteroidal anti-inflammatory drug use Do not use concurrently with tenofovir Not recommended for initial treatment because of low barrier to resistance Should not be used to manage antiviral-resistant hepatitis B Monitoring: Creatinine clearance at baseline; creatinine clearance, serum phosphate, urine glucose, and protein at least annually (if at risk of renal impairment); dual energy x-ray absorptiometry at baseline and during treatment (if history of fracture or at risk of osteopenia); lactic acid levels (if clinical concern); HBV DNA and ALT levels every three months until undetectable, then every three to six months; HBeAg, anti-HBe, HBsAg	Acute renal failure, Fanconi syndrome, nephrogenic diabetes insipidus, lactic acidosis/hepatomegaly	Nucleoside/nucleotide analogues Had a 43% reduction in HBV DNA level and 48% greater normalization of ALT level compared with placebo Had a statistically significant higher rate of HBeAg seroconversion, HBeAg loss, and histologic improvement compared with placebo	$500 ($1,450)
Entecavir (Baraclude) Adults: 0.5 to 1 mg orally per day‡ Children > two years: weight based§	Use caution in patients with renal impairment Monitoring: Lactic acid levels (if clinical concern); HBV DNA and ALT levels every three months until undetectable, then every three to six months; HBeAg, anti-HBe, HBsAg	Lactic acidosis/hepatomegaly		$200 ($1,400) for 1 mg
Lamivudine (Epivir HBV) Adults: 100 mg orally per day Children two years or older: 3 mg per kg (maximum: 100 mg) orally per day	Use caution in patients with renal impairment Monitoring: Amylase (if symptomatic); lactic acid levels (if clinical concern); HBV DNA and ALT levels every three months until undetectable, then every three to six months; HBeAg, anti-HBe, HBsAg Not recommended for initial treatment because of low barrier to resistance	Pancreatitis, lactic acidosis/hepatomegaly, immune reconstitution syndrome, headache, fatigue, fat redistribution		$160 ($500) for 100 mg
Telbivudine (no longer available in the United States) Adults: 600 mg orally per day Children: Not approved	Use caution in individuals who did not respond to previous lamivudine therapy and in those with renal impairment Monitoring: Creatine kinase (if symptomatic); lactic acid levels (if clinical concern); HBV DNA and ALT levels every three months until undetectable, then every three to six months; HBeAg, anti-HBe, HBsAg; clinical monitoring for peripheral neuropathy Safety/effectiveness have not been established in blacks or Hispanics	Myopathy, peripheral neuropathy, lactic acidosis/hepatomegaly		— ($1,100)
Tenofovir disoproxil fumarate (Viread) Adults and children ≥ 12 years and ≥ 35 kg (77.2 lb): 300 mg orally per day Tenofovir alafenamide (Vemlidy) Adults: 25 mg orally per day Children: Not approved	Use caution in patients with renal impairment Monitoring: Same as adefovir	Nephropathy, Fanconi syndrome, osteomalacia, lactic acidosis/hepatomegaly		Tenofovir disoproxil fumarate: $160 ($1,200) Tenofovir alafenamide:— ($1,100)

There are clear advantages and disadvantages to each approach. A meta-analysis including 14 studies involving 2,829 individuals found improved treatment effectiveness with combined therapy (peginterferon alfa-2a and nucleoside/nucleotide analogue); however, because of heterogeneity among trials and lack of consistent evidence, current guidelines recommend monotherapy.²⁸

Subcutaneous Pegylated Interferon Alfa-2a. Pegylated interferon alfa-2a is administered for 48 weeks and should be considered in individuals with predictors of favorable treatment response and who may benefit from a defined treatment duration (e.g., low pretreatment HBV DNA and high ALT levels, HBV genotypes A or B, young women who wish to become pregnant in the future, concomitant hepatitis C, and younger age).^27,28 Pegylated interferon alfa-2a has shown slightly higher seroconversion rates than nucleoside/nucleotide analogues; however, treatment outcomes differ among HBV genotypes.

The primary drawback of peginterferon alfa-2a is tolerability because this therapy is associated with frequent adverse effects (i.e., flulike symptoms, fatigue, mood disturbances, cytopenias, autoimmune disorders in adults, and anorexia and weight loss in children).^2,29 The safety and effectiveness of peginterferon alfa-2a has been demonstrated in several studies conducted in individuals with HBeAg-positive and HBeAg-negative chronic hepatitis B.^30–33

Oral Antiviral Agents. The nucleoside/nucleotide analogues approved in the United States for treatment of chronic hepatitis B are adefovir (Hepsera), entecavir, lamivudine (Epivir HBV), telbivudine (no longer available in the United States), tenofovir disoproxil fumarate (Viread), and tenofovir alafenamide (Vemlidy). These drugs, which target HBV by inhibiting the viral polymerase, are the most commonly used antivirals for treating chronic hepatitis B. They have excellent tolerability and safety profiles; however, the duration of their use is often indefinite because of frequent relapses or reactivation of hepatitis B after cessation of treatment.²⁹ Entecavir, tenofovir, and tenofovir alafenamide are preferred because of their higher antiviral potency and lower resistance rates.²⁷

The 2018 guidelines from the American Association for the Study of Liver Diseases recommend tenofovir alafenamide for initial therapy in adults with immune-active chronic hepatitis B. Tenofovir alafenamide should also be considered in patients with or at risk of renal dysfunction or bone disease. However, it is not recommended for patients who have a creatinine clearance less than 15 mL per minute per 1.73 m² (0.25 mL per second per m²) or who are on dialysis.³⁷ Multiple randomized controlled trials have shown excellent tolerability and effectiveness when comparing entecavir, tenofovir, and tenofovir alafenamide with other nucleoside/nucleotide analogues.^38–42

PREGNANCY

Treating pregnant women who are HBsAg positive reduces perinatal transmission rates. Tenofovir is the preferred antiviral in pregnant women because it has a better resistance profile and there are more safety data in pregnant women with hepatitis B.⁴³ The CDC recommends testing HBsAg-positive pregnant women for HBV-DNA to identify infants at greatest risk of perinatal HBV transmission and to guide maternal antiviral therapy.¹¹

Decompensated Cirrhosis/Liver Transplant

Individuals with decompensated cirrhosis and chronic hepatitis B should be treated with a nucleoside/nucleotide analogue and assessed for liver transplantation eligibility.¹⁹ There is strong evidence that antiviral therapy improves liver function, increases survival, and avoids the need for liver transplantation when anti-HBV treatment is initiated early in decompensated cirrhosis.¹⁹

After liver transplantation to prevent recurrence of hepatitis B, low-risk patients may be treated with nucleoside/nucleotide analogue monotherapy, with or without hepatitis B immune globulin, and high-risk patients should be treated with both hepatitis B immune globulin and a nucleoside/nucleotide analogue.¹⁹

This article updates previous articles on this topic by Wilkins, et al.,^²⁰ and Lin and Kirchner.^⁴⁴

Data sources: We completed a general PubMed search using the MeSH term hepatitis B and excluding the MeSH terms hepatitis C and hepatitis D. The term hepatitis B was also used in a number of specialized searches looking into specific topics in combination with one or more of the following terms: child, pediatric, adult, caregivers, liver disease, liver cancer, treatment, vaccinations, screenings. The search included meta-analyses, randomized-controlled trials, and practice guidelines within the past 20 years. Also searched were the Cochrane database and Essential Evidence Plus. Search dates: October 2017 and November 2018.

Centers for Disease Control and Prevention. Viral hepatitis surveillance. United States, 2015. https://www.cdc.gov/hepatitis/statistics/2015surveillance/pdfs/2015HepSurveillanceRpt.pdf. Accessed February 12, 2018.

Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH American Association for the Study of Liver Diseases. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261-283.

Schillie S, Murphy TV, Sawyer M, et al.; Centers for Disease Control and Prevention. CDC guidance for evaluating health-care personnel for hepatitis B virus protection and for administering postexposure management. MMWR Recomm Rep. 2013;62(RR-10):1-19.

Lin CL, Kao JH. Natural history of acute and chronic hepatitis B: The role of HBV genotypes and mutants. Best Pract Res Clin Gastroenterol. 2017;31(3):249-255.

Li M, Sohn JA, Seeger C. Distribution of hepatitis B virus nuclear DNA. J Virol. 2017;92(1):e01391-17.

Screening for hepatitis B virus infection in pregnancy: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2009;150(12):869-873.

LeFevre ML. Screening for hepatitis B virus infection in nonpregnant adolescents and adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;161(1):58-66.

American Academy of Family Physicians. Clinical preventive service recommendation. Hepatitis. https://www.aafp.org/patient-care/clinical-recommendations/all/hepatitis.html. Accessed October 8, 2018.

Weinbaum CM, Williams I, Mast EE, et al.; Centers for Disease Control and Prevention. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57(RR-8):1-20.

Abara WE, Qaseem A, Schillie S, McMahon BJ, Harris AM. Hepatitis B vaccination, screening, and linkage to care: best practice advice from the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2017;167(11):794-804.

Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67(1):1-31.

Centers for Disease Control and Prevention. Hepatitis B questions and answers for health professionals. https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#D4. Accessed November 3, 2018.

Heplisav-B® (HepB-CpG) vaccine. Advisory Committee on Immunization Practices (ACIP) recommendations. https://www.cdc.gov/vaccines/schedules/vacc-updates/heplisav-b.html. Accessed November 3, 2018.

Kao JH. Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol. 2015;29(6):907-917.

Schillie S, Harris A, Link-Gelles R, Romero J, Ward J, Nelson N. Recommendations of the Advisory Committee on Immunization Practices for use of a hepatitis B vaccine with a novel adjuvant. MMWR Morb Mortal Wkly Rep. 2018;67(15):455-458.

David MC, Ha SH, Paynter S, Lau C. A systematic review and meta-analysis of management options for adults who respond poorly to hepatitis B vaccination. Vaccine. 2015;33(48):6564-6569.

Mantzoukis K, Rodríguez-Perálvarez M, Buzzetti E, et al. Pharmacological interventions for acute hepatitis B infection: an attempted network meta-analysis. Cochrane Database Syst Rev. 2017(3):CD011645.

Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014;384(9959):2053-2063.

European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370-398.

Wilkins T, Zimmerman D, Schade RR. Hepatitis B: diagnosis and treatment. Am Fam Physician. 2010;81(8):965-972.

Aghoram R, Cai P, Dickinson JA. Alpha-foetoprotein and/or liver ultrasonography for screening of hepatocellular carcinoma in patients with chronic hepatitis B. Cochrane Database Syst Rev. 2012(9):CD002799.

Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130(7):417-422.

Tang LS, Covert E, Wilson E, Kottilil S. Chronic hepatitis B infection: a review. JAMA. 2018;319(17):1802-1813.

Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358-380.

Committee on Infectious Disease; Committee on Fetus and Newborn. Elimination of perinatal hepatitis B: providing the first vaccine dose within 24 hours of birth. Pediatrics. 2017;140(3):e20171870.

Schillie S, Murphy TV, Fenlon N, Ko S, Ward JW. Update: shortened interval for postvaccination serologic testing of infants born to hepatitis B-infected mothers. MMWR Morb Mortal Wkly Rep. 2015;64(39):1118-1120.

Ghany MG. Current treatment guidelines of chronic hepatitis B: the role of nucleos(t)ide analogues and peginterferon. Best Pract Res Clin Gastroenterol. 2017;31(3):299-309.

Kim V, Abreu RM, Nakagawa DM, Baldassare RM, Carrilho FJ, Ono SK. Pegylated interferon alfa for chronic hepatitis B: systematic review and meta-analysis. J Viral Hepat. 2016;23(3):154-169.

Arends JE, Lieveld FI, Ahmad S, Ustianowski A. New viral and immunological targets for hepatitis B treatment and cure: a review. Infect Dis Ther. 2017;6(4):461-476.

Marcellin P, Bonino F, Lau GK, et al.; Peginterferon alfa-2a in HBeAg-negative Chronic Hepatitis B Study Group. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a. Gastroenterology. 2009;136(7):2169-2179.e1–4.

Marcellin P, Lau GK, Bonino F, 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(12):1206-1217.

Lau GK, Piratvisuth T, Luo KX, 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(26):2682-2695.

Li WC, Wang MR, Kong LB, Ren WG, Zhang YG, Nan YM. Peginterferon alpha-based therapy for chronic hepatitis B focusing on HBsAg clearance or seroconversion: a meta-analysis of controlled clinical trials. BMC Infect Dis. 2011;11:165.

Bedre RH, Raj U, Misra SP, Varadwaj PK. Antiviral therapy with nucleotide/nucleoside analogues in chronic hepatitis B: A meta-analysis of prospective randomized trials. Indian J Gastroenterol. 2016;35(2):75-82.

Viganò M, Grossi G, Loglio A, Lampertico P. Treatment of hepatitis B: Is there still a role for interferon?. Liver Int. 2018;38(suppl 1):79-83.

Lexicomp.com. https://online.lexi.com/lco/action/home. Accessed November 3, 2018.

Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-1599.

Buti M, Gane E, Seto WK, et al.; GS-US-320-0108 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial [published correction appears in Lancet Gastroenterol Hepatol. 2016;1(3):e2]. Lancet Gastroenterol Hepatol. 2016;1(3):196-206.

Chan HL, Fung S, Seto WK, et al.; GS-US-320-0110 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial [published correction appears in Lancet Gastroenterol Hepatol. 2016;1(3):e2]. Lancet Gastroenterol Hepatol. 2016;1(3):185-195.

Chang TT, Gish RG, de Man R, et al.; BEHoLD AI463022 Study Group. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354(10):1001-1010.

Lai CL, Shouval D, Lok AS, et al.; BEHoLD AI463027 Study Group. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B [published correction appears in N Engl J Med. 2006;354(17):1863]. N Engl J Med. 2006;354(10):1011-1020.

Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359(23):2442-2455.

World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. March 2015. http://www.who.int/hiv/pub/hepatitis/hepatitis-b-guidelines/en/. Accessed October 8, 2018.

Lin KW, Kirchner JT. Hepatitis B [published correction appears in Am Fam Physician. 2004;69(8):1863]. Am Fam Physician. 2004;69(1):75-82.