Hepatitis B PDF

# Hepatitis B ## Clinical Manifestations - People acutely infected with hepatitis B virus (HBV) may be asymptomatic or symptomatic. - The likelihood of developing symptoms of acute hepatitis is age dependent: - Less than 1% of infants younger than 1 year - 5% to 15% of children 1 through 5 yea...

# Hepatitis B ## Clinical Manifestations - People acutely infected with hepatitis B virus (HBV) may be asymptomatic or symptomatic. - The likelihood of developing symptoms of acute hepatitis is age dependent: - Less than 1% of infants younger than 1 year - 5% to 15% of children 1 through 5 years of age - 30% to 50% of people older than 5 years are symptomatic, - The spectrum of signs and symptoms is varied and includes: - Subacute illness with nonspecific symptoms (eg, anorexia, nausea, or malaise) - Clinical hepatitis with jaundice, or fulminant hepatitis. - Extrahepatic manifestations, such as: - Arthralgia - Arthritis - Macular rashes - Thrombocytopenia - Polyarteritis nodosa - Glomerulonephritis can occur early in the course of illness and may precede jaundice. - Papular acrodermatitis (Gianotti-Crosti syndrome) is an extrahepatic manifestation of infection attributable to a number of viral infections, including hepatitis B. - However, since the advent of universal HBV immunization in infants, papular acrodermatitis attributable to HBV is rare; it is more commonly caused by Epstein-Barr virus and less commonly by enteroviruses, cytomegalovirus, parvovirus B19, and others. - Acute HBV infection cannot be distinguished from other forms of acute viral hepatitis on the basis of clinical signs and symptoms or nonspecific laboratory findings. ## Chronic HBV Infection - Chronic HBV infection is defined as persistence in serum for at least 6 months of any one of the following: - Hepatitis B surface antigen (HBsAg) - HBV DNA - Hepatitis B e antigen (HBeAg) - Chronic HBV infection is likely in the presence of HBsAg, HBV DNA, or HBeAg in serum from a person who tests negative for antibody of the immunoglobulin (Ig) M subclass to hepatitis B core antigen (IgM anti-HBc). - Age at the time of infection is the primary determinant of risk of progressing to chronic infection. - Up to 90% of infants infected perinatally or in the first year of life will develop chronic HBV infection. - Between 25% and 50% of children infected between 1 and 5 years of age become chronically infected, - 5% to 10% of infected older children and adults develop chronic HBV infection. - Patients who become HBV infected while immunosuppressed or with an underlying chronic illness (eg, end-stage renal disease) have an increased risk of developing chronic infection. - In the absence of treatment, up to 25% of infants and children who acquire chronic HBV infection will die prematurely from HBV-related hepatocellular carcinoma or cirrhosis. ## Untreated Chronic HBV Infection - The clinical course of untreated chronic HBV infection varies according to the population studied, reflecting differences in: - Age at acquisition - Rate of loss of HBeAg - Possibly HBV genotype. - Most children have asymptomatic infection. - Perinatally infected children usually have normal or minimally elevated alanine transaminase (ALT) concentrations and minimal or mild liver histologic abnormalities, with detectable HBeAg and high HBV DNA concentrations (≥20 000 IU/mL) for years to decades after initial infection. - Children with chronic HBV may exhibit growth impairment. - Chronic HBV infection acquired during later childhood or adolescence usually is accompanied by more active liver disease and increased serum aminotransferase concentrations. - Patients with detectable HBeAg (HBeAg-positive chronic hepatitis B) usually have high concentrations of HBV DNA and HBsAg in serum and are more likely to transmit infection. - Because HBV-associated liver injury is thought to be immune mediated, in people coinfected with human immunodeficiency virus (HIV) and HBV, the return of immune competence with antiretroviral treatment of HIV infection may lead to a reactivation of HBV-related live inflammation and damage. - Over time (years to decades), HBeAg becomes undetectable in many chronically infected people. - This transition often is accompanied by development of antibody to HBeAg (anti-HBe) and decreases in serum HBV DNA and serum aminotransferase concentrations and may be preceded by a temporary exacerbation of liver disease. - These patients have inactive chronic infection but still may have exacerbations of hepatitis. - Serologic reversion (reappearance of HBeAg) is more common if loss of HBeAg is not accompanied by development of anti-HBe; reversion with loss of anti-HBe also can occur. - Some patients who lose HBeAg may continue to have ongoing histologic evidence of liver damage and moderate to high concentrations of HBV DNA (HBeAg-negative chronic hepatitis B). - Patients with histologic evidence of chronic HBV infection, regardless of HBeAg status, remain at higher risk of death attributable to liver failure compared with HBV-infected people with no histologic evidence of liver inflammation and fibrosis. - Resolved hepatitis B is defined as clearance of HBsAg, normalization of serum aminotransferase concentrations, and development of antibody to HBsAg (anti-HBs). - Chronically infected adults clear HBsAg and develop anti-HBs at the rate of 1% to 2% annually; during childhood, the annual clearance rate is less than 1%. - Reactivation of resolved chronic infection is possible if these patients become immunosuppressed and also is well reported among HBsAg-positive patients receiving anti-tumor necrosis factor agents or disease-modifying antirheumatic drugs (12% of patients). ## Etiology - HBV is a partially double-stranded DNA-containing 42-nm-diameter enveloped virus in the family Hepadnaviridae. - Important components of the viral particle include: - An outer lipoprotein envelope containing HBsAg - An inner nucleocapsid consisting of hepatitis B core antigen (HBcAg) ## Epidemiology - HBV is transmitted through infected blood or body fluids. - Although HBsAg has been detected in multiple body fluids including human milk, saliva, and tears, the most potentially infectious include: - Blood - Serum - Semen - Vaginal secretions - Cerebrospinal, synovial, pleural, pericardial, peritoneal, and amniotic fluids. - People with chronic HBV infection are the primary reservoirs for infection. - Common modes of transmission include: - Percutaneous and permucosal exposure to infectious body fluids - Sharing or using nonsterilized needles, syringes, or glucose monitoring equipment or devices - Sexual contact with an infected person - Perinatal exposure to an infected mother - Household exposure to a person with chronic HBV infection. - The risk of HBV acquisition when a susceptible child bites a child who has chronic HBV infection is unknown. - A theoretical risk exists if HBsAg-positive blood enters the oral cavity of the biter, but transmission by this route has not been reported. - Transmission by transfusion of contaminated blood or blood products is rare in the United States because of routine screening of blood donors and viral inactivation of certain blood products before administration. ## Perinatal Transmission - Perinatal transmission of HBV is highly efficient and usually occurs from blood exposures during labor and delivery. - In utero transmission accounts for less than 2% of all vertically transmitted HBV infections in most studies. - Without postexposure prophylaxis, the risk of an infant acquiring HBV from an infected mother as a result of perinatal exposure is 70% to 90% for infants born to mothers who are HBsAg and HBeAg positive; the risk is 5% to 20% for infants born to HBsAg-positive but HBeAg-negative mothers. - Person-to-person spread of HBV can occur in settings involving interpersonal contact over extended periods, such as in a household with a person with chronic HBV infection. - In regions of the world with a high prevalence of chronic HBV infection, transmission between children in household settings may account for a substantial amount of transmission. - The precise mechanisms of transmission from child-to-child are unknown; however, frequent interpersonal contact of nonintact skin or mucous membranes with blood-containing secretions, open skin lesions, or blood-containing saliva are potential means of transmission. - Transmission from sharing inanimate objects, such as razors or toothbrushes, also may occur. - HBV can survive in the environment for 7 or more days but is inactivated by commonly used disinfectants, including household bleach diluted 1:10 with water. - HBV is not transmitted by the fecal-oral route. - Transmission among children born in the United States is unusual because of high coverage with hepatitis B (HepB) vaccine administered at birth. - Screening mothers during pregnancy for HBV infection allows for additional immunoprophylaxis with Hepatitis B Immune Globulin (HBIG), which, when administered with the hepatitis B vaccine in the immediate newborn period, enhances prevention of mother-to-infant HBV transmission. ## Risk Factors for HBV Infection - The risk of HBV transmission is higher in children who have not completed a vaccine series, children undergoing hemodialysis, institutionalized children with developmental disabilities, and children emigrating from regions and countries with endemic HBV (eg, Southeast Asia, China, Africa). - Person-to-person transmission has been reported in childcare settings, but risk of transmission in childcare facilities in the United States has become negligible as a result of high infant hepatitis B immunization rates. - Acute HBV infection is reported most commonly among adults 30 through 49 years of age in the United States. - Since 1990, the incidence of acute HBV infection has decreased in all age categories, with a 98% decline in children younger than 19 years and a 93% decline in young adults 20 through 29 years of age, with most of the decrease among people 20 through 24 years of age. - Current statistics on hepatitis B case numbers and incidence rates can be found at www.cdc.gov/hepatitis/statistics/2015surveillance/index.htm. -People at high risk for acute hepatitis B virus infection include: - People who inject drugs - People with multiple sexual partners - Men who have sex with men - People who reported surgery during the 6 weeks to 6 months before onset of symptoms - Others at increased risk include: - People with occupational exposure to blood or body fluids - Staff of institutions and nonresidential child care programs for children with developmental disabilities - Patients undergoing hemodialysis - Sexual or household contacts of people with an acute or chronic infection - Approximately 62% of case reports in 2014 with risk exposure or behavior information did not have a readily identifiable risk characteristic. - HBV infection in adolescents and adults is associated with other sexually transmitted infections, including syphilis and HIV infection. - Investigations have indicated an increased risk of HBV infection among adults with diabetes mellitus. - Outbreaks in nonhospital health care settings, highlight the increased risk among people with diabetes mellitus undergoing assisted blood glucose monitoring. ## Prevalence of HBV Infection - The prevalence of HBV infection and patterns of transmission vary markedly throughout the world. - Approximately 45% of people worldwide live in regions of high HBV endemicity, where the prevalence of chronic HBV infection is 8% or greater. - Historically in these regions, most new HBV infections occurred as a result of perinatal or early childhood infections. - In regions of intermediate HBV endemicity, where the prevalence of HBV infection is 2% to 7%, multiple modes of transmission (ie, perinatal, household, sexual, injection drug use, and health care associated) contribute to the burden of infection. - In countries with low endemicity, where chronic HBV infection prevalence is less than 2% (including the United States) and where routine immunization has been adopted, new infections increasingly occur among unimmunized age groups. - Many people born in countries with high endemicity live in the United States. - Infant immunization programs in some of these countries have, in recent years, greatly reduced the seroprevalence of HBsAg, but many other countries with endemic HBV have yet to implement widespread routine childhood hepatitis B immunization programs. ## Incubation Period - The incubation period for acute HBV infection is 45 to 160 days, with an average of 90 days. ## Diagnostic Tests - Serologic protein antigen tests are available commercially to detect HBsAg and HBeAg. - Serologic antibody assays also are available for detection of: -anti-HBs - total anti-HBc - IgM anti-HBc - anti-HBe. - Nucleic acid amplification testing (NAAT), polymerase chain reaction (PCR) assay, and branched DNA methods as well as hybridization assays are available to detect and quantify HBV DNA in plasma or serum. - At least 2 PCR assays for quantitative detection of HBV DNA are cleared by the US Food and Drug Administration (FDA). - These assays are used to monitor patients with chronic HBV infection and to evaluate their response to treatment regimens. - The assays differ in their limits of detection, dynamic range, and target gene sequences detected. - Because of variability in the different assays, it is best to use the same manufacturer's assay performed in the same laboratory to monitor an individual's patient's HBV load. - Tests to quantify HBsAg and HBeAg currently are being developed but are not yet available commercially. ## Table 3.19: Estimated International HBsAg Prevalence | Region | Estimated HBsAg Prevalence | |------------------------------|-------------------------| | North America | 0.1% | | Mexico and Central America | 0.3% | | South America | 0.7% | | Western Europe | 0.7% | | Australia and New Zealand | 0.9% | | Caribbean (except Haiti) | 1.0% | | Eastern Europe and North Asia | 2.8% | | South Asia | 2.8% | | Middle East | 3.2% | | Haiti | 5.6% | | East Asia | 7.4% | | Southeast Asia | 9.1% | | Africa | 9.3% | | Pacific Islands | 12.0% | *HBsAg indicates hepatitis B surface antigen.* *Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1-33.* *Level of HBV endemicity defined as high (≥8%), intermediate (2%-7%), and low (<2%).* ## Table 3.20: Diagnostic Tests for Hepatitis B Virus (HBV) Antigens and Antibodies | Factors To Be Tested | HBV Antigen or Antibody | Use | |-------------------------|--------------------------|--------------------------------------------------------------------------| | HBsAg | Hepatitis B surface antigen | Detection of acutely or chronically infected people; antigen used in hepatitis B vaccine; can be detected for up to 3 weeks after a dose of hepatitis B vaccine | | Anti-HBs | Antibody to HBsAg | Identification of people who have resolved infections with HBV; determination of immunity after immunization | | HBeAg | Hepatitis B e antigen | Identification of infected people at increased risk of transmitting HBV | | Anti-HBe | Antibody to HBeAg | Identification of infected people with lower risk of transmitting HBV | | Anti-HBc (total) | Antibody to HBcAg | Identification of people with acute, resolved, or chronic HBV infection (not present after immunization; passively transferred maternal anti-HBc is detectable for as long as 24 months among infants born to HBsAg-positive women) | | IgM anti-HBc | IgM antibody to HBcAg | Identification of people with acute or recent HBV infections (including HBsAg-negative people during the "window" phase of infection; unreliable for detecting perinatal HBV infection) | *HBcAg indicates hepatitis B core antigen; IgM, immunoglobulin M.* *No test is available commercially to measure HBcAg.* ## Treatment - No specific therapy for uncomplicated acute HBV infection is available, and acute HBV infection usually does not warrant referral to a hepatitis specialist unless there is progression to acute liver failure. - In that situation, treatment with a nucleoside or nucleotide analogue is indicated. - Acute HBV infection may be difficult to distinguish from reactivation of HBV. - If reactivation is a possibility, referral to a hepatitis specialist would be warranted. - HBIG and corticosteroids are not effective treatment for acute or chronic disease. ## Chronic HBV Infection Treatment - Children and adolescents who have chronic HBV infection are at risk of developing serious liver disease, including primary hepatocellular carcinoma (HCC), with advancing age and, therefore, should receive hepatitis A vaccine. - Although the peak incidence of primary HCC attributable to HBV infection is in the fifth decade of life, HCC occurs in children as young as 6 years who became infected perinatally or in early childhood. - Several algorithms have been published describing the initial evaluation, monitoring, and criteria for treatment. - Children with chronic HBV infection should be screened periodically for hepatic complications using serum aminotransferase tests, alpha-fetoprotein concentration, and abdominal ultrasonography. - Definitive recommendations on the frequency and indications for specific tests are not yet available because of a lack of data on their reliability in predicting sequelae. - Patients with serum ALT concentrations persistently exceeding the upper limit of normal and patients with an increased serum alpha-fetoprotein concentration or abnormal findings on abdominal ultrasonography should be referred to a specialist in the management of chronic HBV infection. The goal of treatment in chronic HBV infection is to prevent progression to cirrhosis, hepatic failure, and HCC. Current indications for treatment of chronic HBV infection include evidence of ongoing HBV viral replication, as indicated by the presence for longer than 6 months of serum HBV DNA greater than 20 000 IU/mL without HBeAg positivity, greater than 2000 IU/mL with HBeAg positivity, and elevated serum ALT concentrations for longer than 6 months or evidence of chronic hepatitis on liver biopsy. Children without necroinflammatory liver disease and children with immunotolerant chronic HBV infection (ie, normal ALT concentrations despite the presence of HBV DNA) usually do not warrant antiviral therapy. Treatment response is measured by biochemical, virologic, and histologic response. An important consideration in the choice of treatment is to avoid selection of antiviral-resistant mutations. The FDA has approved 3 nucleoside analogues (entecavir, lamivudine, and telbivudine), 2 nucleotide analogues (tenofovir and adefovir), and 2 interferon-alfa drugs (interferon alfa-2b and pegylated interferon alfa-2a) for treatment of chronic HBV infection in adults. Tenofovir, entecavir, and pegylated interferon alfa-2a are preferred in adults as first-line therapy because of the lower likelihood of developing antiviral resistance mutations over long-term therapy. Of these, FDA licensure in the pediatric population is as follows: interferon alfa-2b, ≥1 year of age; lamivudine and entecavir, ≥2 years of age; adefovir and tenofovir disproxil fumarate, ≥12 years of age; and telbivudine, ≥16 years of age. Pediatric trials of telbivudine, tenofovir, and pegylated interferon currently are underway. Pegylated interferon alfa-2a is not approved for children with chronic HBV but is approved for children ≥5 years of age to treat chronic hepatitis C infection. Specific therapy guidelines for children coinfected with HIV and HBV can be accessed online (https://aidsinfo.nih.gov/guidelines). Developments in antiviral therapies of HBV may be found on the American Association for the Study of Liver Diseases Web site (www.aasld.org). The optimal agent(s) and duration of therapy for chronic HBV infection in children remain unclear. There are few large randomized controlled trials of antiviral therapies for chronic hepatitis B in childhood. Studies indicate that approximately 17% to 58% of children with increased serum aminotransferase concentrations who are treated with interferon alfa-2b for 6 months lose HBeAg, compared with approximately 8% to 17% of untreated controls. Response to interferon-alfa is better for children from Western countries (20%-58%) as compared with Asian countries (17%). Children from Asian countries with HBV infection are more likely to: (1) have acquired infection perinatally; (2) have a prolonged immune-tolerant phase of infection; and (3) be infected with HBV genotype C. All 3 of these factors are associated with lower response rates to interferon-alfa, which is less effective for chronic infections acquired during early childhood, especially if serum aminotransferase concentrations are normal. Children with chronic HBV infection who were treated with lamivudine had higher rates of virologic response (loss of detectable HBV DNA and loss of HBeAg) after 1 year of treatment than did children who received placebo (23% versus 13%). Resistance to lamivudine can develop during treatment and may occur early. The high rates of lamivudine resistance (~70% after 3 years of therapy) have decreased enthusiasm for the use of this drug. Children coinfected with HIV and HBV should receive the lamivudine dose approved for treatment of HIV. Consultation with health care professionals with expertise in treating chronic hepatitis B in children is recommended. ## Isolation of the Hospitalized Patient - Standard precautions are indicated for patients with acute or chronic HBV infection. - For infants born to HBsAg-positive mothers, no special care in addition to standard precautions, as described under Control Measures, is needed, other than removal of maternal blood by a gloved attendant. ## Control Measures - Strategy for Prevention of HBV Infection. The primary goal of hepatitis B-prevention programs is to eliminate transmission of HBV, thereby decreasing rates of chronic HBV infection and HBV-related chronic liver disease. A secondary goal is prevention of acute HBV infection. In the United States over the past 2 decades, a comprehensive immunization strategy to eliminate HBV transmission has been implemented progressively and now includes the following 4 components: (1) universal immunization of infants beginning at birth; (2) prevention of perinatal HBV infection through routine screening of all pregnant women and appropriate immunoprophylaxis of infants born to HBsAg-positive mothers; (3) routine immunization of children and adolescents who previously have not been immunized; and (4) immunization of previously unimmunized adults at increased risk of infection. - Hepatitis B Immunoprophylaxis. Two types of products are available for immunoprophylaxis. HBIG provides short-term protection (3-6 months) and is indicated only in specific postexposure circumstances. HepB vaccine is used for preexposure and postexposure protection and provides long-term protection. Preexposure immunization with HepB vaccine is the most effective means to prevent HBV transmission. Accordingly, HepB immunization is recommended for all infants, children, and adolescents through 18 years of age. Infants should receive HepB vaccine as part of the routine childhood immunization schedule. All children 11 through 12 years of age should have their immunization records reviewed and should complete the HepB vaccine series if they have not received the vaccine or did not complete the immunization series. - For infants born to women who are positive for both HBsAg and HBeAg, postexposure immunoprophylaxis either with HepB vaccine and HBIG or with HepB vaccine alone effectively prevents most infections after exposure to HBV. Use of both HepB vaccine and HBIG appears to provide greater protection than HepB vaccine alone. Effectiveness of postexposure immunoprophylaxis is related directly to the time elapsed between exposure and administration. Immunoprophylaxis of perinatal infection is most effective if administered within 12 hours of birth; data are limited on effectiveness when administered between 25 hours and 7 days of life. Serologic testing of all pregnant women for HBsAg early (eg, first trimester) during each pregnancy is essential for identifying women whose infants will require postexposure immunoprophylaxis beginning at birth. - Hepatitis B Immune Globulin. HBIG is prepared from plasma of donors with high concentrations of anti-HBs, with an anti-HBs titer of at least 1:100 000 by radioimmunoassay. Plasma donors are required to have negative serologic and nucleic acid test results for HIV and HCV. Additionally, the processes used to manufacture HBIG products are demonstrated to inactivate HBV, HIV, and HCV. Standard Immune Globulin is not effective for postexposure prophylaxis against HBV infection, because concentrations of anti-HBs are too low. - Hepatitis B Vaccine. Highly effective and safe HepB vaccines produced by recombinant DNA technology are licensed in the United States in single-antigen formulations and as components of combination vaccines. Plasma-derived HepB vaccines no longer are available in the United States but may be used successfully in a few countries. Recombinant vaccines contain 10 to 40 µg of HBsAg protein/mL, and a completed vaccine series results in production of anti-HBs of at least 10 mIU/mL in most people, which provides long-term protection for immunocompetent recipients. Single-dose formulations, including all pediatric formulations, contain no thimerosal as a preservative. Although the concentration of recombinant HBsAg protein differs among vaccine products, rates of seroprotection are equivalent when administered to immunocompetent infants, children, adolescents, or young adults in the doses recommended. - HepB vaccine can be administered concurrently with other vaccines (see Simultaneous Administration of Multiple Vaccines). - Vaccine Interchangeability. In general, the various brands of age-appropriate HepB vaccines are interchangeable within an immunization series. The immune response using 1 or 2 doses of a vaccine produced by one manufacturer followed by 1 or more subsequent doses from a different manufacturer is comparable to a full course of immunization with a single product. . However, until additional data supporting interchangeability of acellular pertussis-containing HepB combination vaccines are available, vaccines from the same manufacturer should be used, whenever feasible, for at least the first 3 doses in the pertussis series. In addition, a 2-dose schedule of the adult formulation of Recombivax HB (Merck & Co., Whitehouse Station, NJ) is licensed for adolescents 11 through 15 years of age. - Routes of Administration. Vaccine is administered intramuscularly in the anterolateral thigh for infants or deltoid area for children and adults. Administration in the buttocks or by the intradermal route is not recommended at any age. - Efficacy and Duration of Protection. HepB vaccines licensed in the United States have a 90% to 95% efficacy for preventing HBV infection and clinical HBV disease among susceptible children and adults. Immunocompetent people who achieve anti-HBs concentration ≥10 mIU/mL after preexposure vaccination have virtually complete protection against infection with HBV. Long-term studies of immunocompetent adults and children indicate that immune memory remains intact for 2 decades and protects against symptomatic acute and chronic HBV infection, even though anti-HBs concentrations may become low or undetectable over time. Breakthrough infections. Chronic HBV infection in immunized people has been documented in dialysis patients whose anti-HBs concentrations fell below 10 mIU/mL and rarely among people who did not respond to vaccination (eg, adults and infants born to HBsAg-positive mothers). - Booster Doses. For children and adults with normal immune status, routine booster doses of HepB vaccine are not recommended. . For patients undergoing hemodialysis who are at continued risk of infection, the need for booster doses should be assessed by annual anti-HBs testing, and a booster dose should be administered when the anti-HBs concentration is <10 mIU/mL. Annual anti-HBs testing and booster doses when anti-HBs concentrations decrease to <10 mIU/mL should be considered for immunocompromised people if they have an ongoing risk for HBV exposure. Similar consideration may be given to children with cystic fibrosis, liver disease, or celiac disease if there is an ongoing risk for HBV exposure. Children with celiac disease may not respond as well to HepB vaccine. - Adverse Events. Adverse effects most commonly reported in adults and children are pain at the injection site, reported by 3% to 29% of recipients, and a temperature greater than 37.7°С (99.8°F), reported by 1% to 6% of recipients. Anaphylaxis is uncommon, occurring in approximately 1 in 1.1 million recipients. - Immunization During Pregnancy or Lactation. No adverse effect on the developing fetus has been observed when pregnant women have been immunized. Because HBV infection may result in severe disease in the mother and chronic infection in the newborn infant, pregnancy is not a contraindication to immunization. Lactation is not a contraindication to immunization. - Serologic Testing. Susceptibility testing before immunization is not indicated routinely for children or adolescents. Testing for past or current infection may be considered for people in risk groups with high rates of HBV infection, including people born in countries with intermediate and high HBV endemicity (even if immunized, because the entire immunization series may not have been completed or the person may have failed to respond to the immunization), users of injection drugs, men who have sex with men, and household and sexual contacts of HBsAg-positive people, provided testing does not delay or impede immunization efforts. A substantial proportion of people with chronic HBV infection are unaware of their infection. - Routine postimmunization testing for anti-HBs is not necessary after routine vaccination of healthy people but is recommended 1 to 2 months after the final vaccine dose for the following specific groups: (1) hemodialysis patients; (2) people with HIV infection; (3) people at occupational risk of exposure from percutaneous injuries or mucosal or nonintact skin exposures (eg, certain health care and public safety workers); (4) other immunocompromised patients (eg, hematopoietic stem-cell transplant recipients or people receiving chemotherapy); and (5) sexual partners of HBsAg-positive people. If anti-HBs testing is performed on health care personnel at a time distant from immunization (ie, at the time of hire or matriculation for health care personnel vaccinated as an infant), further management is described in Fig 3.4. If immunized health care personnel are exposed to blood or body fluids from a person who is HBsAg-positive, management of the exposure is described in Table 3.22. - Testing of infants born to HBsAg-positive mothers should occur at 1 to 2 months after the last vaccine dose; these infants should have postimmunization testing for HBsAg and anti-HBs performed at 9 to 12 months of age, generally at the next well-child visit after completion of the vaccine series. Testing should not be performed before 9 months of age to maximize the likelihood of detecting late-onset HBV infections. HBsAg-negative infants with anti-HBs titers <10 mIU/mL after completing the 3-dose vaccine series should be revaccinated with a single dose of HepB vaccine and retested for anti-HBs antibody titers 1 to 2 months later. Infants who have anti-HBs titers ≥10 mIU/mL after this fourth dose of HepB vaccine do not need any additional doses of the HepB vaccine. Infants who fail to reach anti-HBs titers ≥10 mIU/mL after the fourth dose of HepB vaccine should receive 2 additional doses of the HepB vaccine followed by retesting for anti-HBs antibody titers 1 to 2 months later. An alternate approach for children who have completed a 3-dose series of HepB vaccine but did not achieve anti-HBs titers ≥10 mIU/mL is to give 3 additional doses of HepB vaccine and then retest for anti-HBs titers 1to 2 months after the third dose of this second series. Currently available data do not suggest any benefit from administration of additional HepB vaccine doses to infants who do not attain anti-HBs titers ≥10 mIU/mL following receipt of 2 complete 3-dose series (total of 6 doses) of HepB vaccine. For these infants, no additional HepB vaccine doses are recommended. - Management of Nonresponders. Vaccine recipients who do not develop a serum anti-HBs response (≥10 mIU/mL) after a primary vaccine series should be tested for HBsAg to rule out the possibility of a chronic infection as an explanation of failure to respond to the vaccine. If the HBsAg test result is negative, their management is detailed in Serologic Testing, Fig 3.4, and Table 3.22 for health care personnel and Table 3.23 for nonoccupational exposures. Fewer than 5% of immunocompetent infants, children, and young adults receiving 6 doses of HepB vaccine administered appropriately fail to develop detectable antibody. People who remain anti-HBs negative 1 to 2 months after a reimmunization series are unlikely to respond to additional doses of vaccine and should be considered nonimmune if they are exposed to HBV in the future. - Altered Doses and Schedules. Larger vaccine doses are required to induce protective anti-HBs concentrations in adult hemodialysis patients and immunocompromised adults, including HIV-seropositive people. Humoral immune response to HepB vaccine also may be reduced in children and adolescents who are receiving hemodialysis or who are immunocompromised. However, few data exist concerning the response to higher doses of vaccine in children and adolescents, and no specific recommendations can be made for these age groups. For unvaccinated people with progressive chronic renal failure, and possibly cardiac or other transplant recipients, HepB vaccine should be administered as early as possible in the disease course to provide protection and potentially improve responses to vaccination. - Preexposure Universal Immunization of Infants, Children, and Adolescents. Immunization with HepB vaccine is recommended for all infants, children, and adolescents through 18 years of age, administered as a series of 3 doses (0.5 mL/dose) on a 0-, 1-, and 6-month schedule. Age-specific vaccine dosages are provided in Table 3.21. Delivery hospitals should develop policies and procedures that ensure administration of a birth dose within 24 hours of age as part of the routine care of all medically stable infants weighing 2000 g or more at birth. For all medically stable infants weighing ≥2000 g at birth, regardless of mother's HBsAg status, the first dose of vaccine should be administered within 24 hours of birth. Deferral to a time after birth or discharge from the hospital no longer is considered to be an acceptable option, because it might deprive an HBV-exposed infant of timely administration of HBV prophylaxis. Determination of timing of the first dose of hepatitis B vaccine is predicated on the infant's birth weight and the mother's hepatitis B surface antigen status. Table 3.24 details the appropriate timing of the first hepatitis B vaccine dose for infants weighing ≥2000 g and for infants <2000 g and infants born to mothers who are HBsAg-negative, HBsAg-positive, and HBsAg-unknown. Timing of administration of HBIG, if appropriate, also is detailed in the table. For preterm infants weighing <2000 g, the initial vaccine dose should not be counted in the required 3-dose schedule (a total of 4 doses of HepB vaccine should be administered), and the subsequent 3 doses should be administered in accordance with the schedule for immunization of infants weighing <2000 g. Only single-antigen HepB vaccine should be used for the birth dose. The HepB vaccine series for infants born to HBsAg-negative mothers should be completed by 6 to 18 months of age. All children and adolescents who have not been immunized against HBV should begin the series during any visit. - High seroconversion rates and protective concentrations of anti-HBs (10 mIU/mL or greater) are achieved when HepB vaccine is administered in any of the various recommended schedules, including schedules begun soon after birth in term infants. Only single-antigen HepB vaccine can be used for doses administered between birth and 6 weeks of age. Single-antigen or combination vaccine may be used to complete the series; 4 doses of vaccine may be administered if a birth dose is administered and a combination vaccine containing a hepatitis B component is used to complete the series. For guidelines for minimum scheduling time between vaccine doses for infants, see Table 1.11. For immunizations of older children and adolescents, alternate administration schedules at 0, 1, and 4 months may be used (although shorter intervals between first and last doses result in lower immunogenicity). For younger children (birth through 10 years of age), an alternate administration schedule at 0, 1, 2, and 12 months is licensed for one single-antigen HepB vaccine. For older children and adolescents (5 through 16 years of age), an alternate administration schedule at 0, 12, and 24 months and for older children and adolescents (11 through 19 years of age), an alternate dosage (1.0 mL) and administration schedule at 0, 1, 2, and 12 months are licensed for one single-antigen HepB vaccine. A 2-dose alternate dosage (1.0 mL) and administration schedule at 0 and