Adolescent Health Care: A Practical Guide

Chapter 30

Hepatitis

Praveen S Goday

Etiology

Hepatitis may be caused by viral agents such as hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), delta virus (HDV), hepatitis E virus (HEV), Epstein-Barr virus, cytomegalovirus, or noninfectious causes such as hepatotoxins. This chapter discusses primarily hepatitis A, hepatitis B, and hepatitis C.

  1. HAV: Hepatitis A is caused by an RNA virus belonging to the family Picornaviridae.
  2. HBV: Hepatitis B is caused by a 42-nm diameter virus, with an outer lipid envelope surrounding the inner core containing the DNA genome (Fig. 30.1). Several components of this virus can be detected by electron microscopy:
  3. Dane particle: This is the whole 42-nm diameter virus.
  4. A 7-nm thick shell contains the hepatitis B surface antigen (HBsAg).
  5. A 28-nm nucleocapsid: This central core contains the hepatitis B core antigen (HBcAg).
  6. Peripheral blood also contains 20- to 22-nm spherical and tubular particles that contain HBsAg and represent excess virus coat material.
  7. HCV: This is an RNA virus of the Flaviviridae family. It has great genetic heterogeneity, with at least six major genotypes, more than 80 subtypes, and numerous minor variants called quasispecies. There is a genotype-dependent differential response to therapy.
  8. HDV: This is an HBsAg-coated 35- to 37-nm diameter particle that is a “defective” pathogen because it is dependent on the presence of hepatitis B to cause an infection.
  9. HEV: This is an RNA virus that causes fecal-orally transmitted hepatitis in developing countries.

Epidemiology

Table 30.1 outlines the epidemiology of the hepatitis viruses. A more detailed discussion follows.

Hepatitis A

Hepatitis A is transmitted primarily by the fecal-oral route and through contaminated food or water. Infection through personal contact may occur during sexual intercourse or close contact within households. Percutaneous or transfusion-related transmission is extremely rare. Children generally shed the virus longer than adults and asymptomatically infected young children excreting HAV are an important source. Maximum concentrations of virus are excreted in the 2 weeks before the onset of symptoms. Patients are usually considered noninfectious 1 week after onset of jaundice. In the United States, approximately 10% to 20% of individuals have evidence of prior infection by 20 years of age, and approximately 50% by age 50.

Hepatitis B

HBV has been documented in almost all bodily secretions, including tears, stools, saliva, blood, bile, breast milk, vaginal secretions, urine, sneeze droplets, and semen. Transmission occurs through percutaneous or permucosal routes, by infective blood or body fluids, through sexual contact, by contaminated needles, or perinatally from mother to infant. Infection can also occur in settings of continuous close personal contact (such as institutions for persons with developmental disabilities or in households), presumably through inapparent or unnoticed contact of infective secretions with skin lesions or mucosal surfaces.

In the United States, the prevalence of HBsAg is 0.3% and the number of chronically infected persons is estimated at 1.25 million. From 1990 through 2004, the incidence of reported acute hepatitis B in all ages declined by 68% reflecting the success of the national strategy to eliminate hepatitis B, which included screening of pregnant women and postexposure prophylaxis to appropriate infants, routine vaccination of all infants and children younger than 19, and vaccination of others at increased risk of hepatitis B. Since 1990 through 2004, rates among adolescents aged 14 to 18 years have declined approximately 94%, but the 2004 rate (0.4 per 100,000 population) remains substantially higher than the rate for children younger than 13 years (0.07/100,000). Age-specific rates of hepatitis B in the United States increase through adolescence, peaking among young adults. Similar to adults, the most frequently reported risk factors for hepatitis B among adolescents are sexual contact and injection drug use. Risk factors for infection are not always identified.

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FIGURE 30.1 Hepatitis B virion (Dane particle) and spherical and tubular HBsAg particles found in serum of infected persons. HBcAg, and HBsAg: hepatitis B core, and surface antigens, respectively. (Adapted from Kalser MH, Howard RB. Hepatic and pancreatic disorders. Postgrad Med 1986;79:199.)

TABLE 30.1
Clinical and Epidemiological Comparison of Hepatitis Viruses

Characteristics

Hepatitis A

Hepatitis B

Hepatitis C

Hepatitis D

Hepatitis E

From Koff RS. Hepatitis B today: clinical and diagnostic overview. Pediatr Infect Dis J 1993;12:428. Adapted from Hoofnagle JH. Type B hepatitis: virology, serology, and clinical course. Semin Liver Dis 1981;1:1.

Transmission

         

 Usual

Fecal-oral

Parenteral

Parenteral

Parenteral

Fecal-oral

 Alternative

Parenteral (rare)

Frequently nonparenteral (venereal, perinatal)

Venereal, perinatal

Venereal

Possibly parenteral

Distribution

Point-source outbreaks, random cases

Prevalent in young adults and urban populations

Injection drug use, venereal, perinatal

Worldwide; not highly endemic in the United States

Primarily Asia, Africa, Mexico; rare in the United States

Incubation period (d)

15–50

45–160

49–63

Coinfection, 45–60

15–60

       

Superinfection, 14–136

 

Onset

Acute

Often insidious

Insidious

Acute or insidious

Acute

Severity

Usually mild, often anicteric

More severe than hepatitis A; less often anicteric

Mild to moderate

Often severe or fulminant

Variable; severe in pregnancy

Chronic disease

None

90% of perinatal cases; 10% of adult cases

50%–60% of cases

Yes

None

Carrier state

None

Yes

Yes

Yes

None

Case-fatality rate

0%–0.2%

0.3%–15%

Unknown

Unknown

Unknown

Estimated incidence trend in the United States

Decreasing

Decreasing

Decreasing

Unknown

Not endemic in the United States

Estimated proportion of acute hepatitis cases in the United States

~25%

~50%

~20%

Unknown

None

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Hepatitis C

The prevalence of antibodies to HCV in the United States is approximately 2%. Injection drug use is currently responsible for most HCV transmission in the United States. The prevalence of antibodies to HCV in most studies of injection drug users is 80% to 90%, and incidence rates generally range from 10% to 20%/year. Currently, 68% of HCV transmission in the United States is attributable to injection drug use, 18% is associated with sexual exposure, 4% is associated with occupational exposure, 1% is from other exposures (iatrogenic and perinatal), while 9% of transmissions have no definable source. Approximately 5% of infants born to infected mothers become infected. Screening of organ, tissue, and blood donors for HCV has essentially eliminated the risk of transmission in transplantation and transfusion. Likewise, inactivation procedures introduced in the manufacture of clotting factor concentrates have virtually eliminated the risk of infection in the hemophilic population.

Delta Hepatitis

HDV can cause disease only if HBV is present. The transmission of the virus is usually similar to that of HBV(i.e., blood or body fluids). Risk groups include intravenous drug users, male homosexuals, hemodialysis workers and patients, and recipients of blood products.

Hepatitis E

Hepatitis E is a fecal-orally transmitted form of viral hepatitis seen primarily in developing countries in central Asia, Africa, and Mexico. It has a variable presentation but is somewhat more severe than hepatitis A, with fulminant hepatitis occurring in 1% to 3% of patients overall, but in 20% of pregnant women. Although reported cases of hepatitis E have been identified in the United States, transmission is rare here. HEV will not be discussed further in this chapter.

Clinical Manifestations

Symptoms

It is not possible to distinguish among the types of hepatitis on the basis of clinical manifestations. If the date of exposure is known, incubation periods may be helpful in diagnosis:

Hepatitis A

15–50 d, average 28 d

Hepatitis B

42–168 d, average 112 d

Hepatitis C

14–182 d, average 49 d

Hepatitis E

15–60 d, average 40 d

The incubation periods of the three major hepatitis viruses can be remembered more readily as hepatitis A: 2 to 6 weeks, hepatitis B: 2 to 6 months, and hepatitis C: 2 weeks to 6 months.

Common early symptoms of viral hepatitis include fatigue, lassitude, anorexia, nausea, dark urine, drowsiness, low-grade fever, right upper abdominal discomfort, myalgia, and arthralgias. In hepatitis A, approximately 20% of individuals have a history of diarrhea. In viral hepatitis B, immune complexes can lead to arthralgias, arthritis, and a rash. The arthritis of hepatitis B may precede the jaundice. It is usually a symmetrical polyarthritis affecting small joints. Larger joints may be affected, but the feet are usually spared. The rash accompanying hepatitis B occurs in up to 50% of patients and is usually urticarial in nature but may be maculopapular or petechial.

Signs

  1. Icteric sclera
  2. Tender hepatomegaly
  3. Splenomegaly (10% of cases)
  4. Arthritis
  5. Skin rash

Laboratory Findings

  1. Relative lymphocytosis
  2. Elevated serum transaminases
  3. Elevation in total and conjugated bilirubin
  4. Mild elevation in serum alkaline phosphatase
  5. Severe disease: Decreased serum albumin and prothrombin time. Prothrombin time is the only test that has prognostic significance in hepatitis.
  6. Hepatitis B arthritis: Decreased serum and joint complement. White blood cell count in joint fluid ranges between 2,000 and 90,000/mL.

Viral Antigens and Antibodies

To understand the clinical course and diagnosis of viral hepatitis, one must understand the various antigens and antibodies and their clinical significance.

  1. Hepatitis A (Fig. 30.2 and Table 30.2)
  2. Immunoglobulin M (IgM) anti-hepatitis A viral antibody (IgM anti-HAV): This antibody is detected early in the illness and remains detectable for approximately 2 to 3 months.
  3. Immunoglobulin G anti-hepatitis A viral antibody (IgG anti-HAV): This antibody rises more slowly and persists for years. It indicates a past infection and the presence of immunity to HAV.
  4. HAV in stool: This is usually present before the onset of clinical symptoms and is of little clinical utility.
  5. Hepatitis B (Fig. 30.3 and Table 30.2)
  6. HBsAg: The surface antigen becomes positive during the incubation period and disappears in most patients during the course of the clinical disease. However, in certain patients, this antigen may remain positive for life. A positive test result for HBsAg indicates either an acute hepatitis B infection or a chronic carrier state and signifies that the patient is capable of transmitting HBV.
  7. Anti-hepatitis B surface antigen (anti-HBs): This antibody usually becomes positive months after the onset of the clinical disease. A positive blood test result indicates past infection or immunity from immunization. If acute hepatitis is present, the patient probably has hepatitis of another etiology.
  8. HBcAg: The core antigen is not routinely assayed for in peripheral blood.

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FIGURE 30.2 Course of hepatitis A infection. ANTI-HAV, anti-hepatitis A viral antibody; IgG, immunoglobulin G; IgM, immunoglobulin M; SGPT, alanine transaminase. (Adapted from Centers for Disease Control and Prevention. Hepatitis Surveillance Report No. 42. June 1978.)

TABLE 30.2
Interpretation of Hepatitis Antibody Test Results

IgM Anti-HAV

IgG Anti-HAV

HBsAg

Anti-HBc (IgM)

Anti-HBc (IgG)

Interpretation

Anti-HAV, antibody to hepatitis A virus; anti-HBc, antibody to hepatitis B core antigen; HBsAg, hepatitis B surface antigen; Ig, immunoglobulin.

+

-

-

-

-

Acute hepatitis A

-

+

-

-

-

Prior hepatitis A infection

         

• Person is immune to hepatitis A

-

-

+

-

-

Acute hepatitis B; early state or chronic carrier with hepatitis of another origin

-

-

+

+

+

Acute hepatitis B

-

-

+

-

+

Chronic carrier state

-

-

-

+

+

Recent hepatitis B

-

-

-

-

-

Non-A, non-B hepatitis, other viruses, or other causes

 

FIGURE 30.3 Course of hepatitis B infection. Pattern of symptoms and serological tests. ALT, alanine aminotransferase; Anti-HBc, hepatitis B core antibody; Anti-HBe, hepatitis B e antibody; Anti-HBs, hepatitis B surface antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; Ig, immunoglobulin. (From Hollinger FB. Hepatitis markers: guide to test selection. Diagnosis 1986;Aug:58.)

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  2. Anti-hepatitis B core antigen (anti-HBc): This antibody appears as HBsAg is falling and before anti-HBs appears. Anti-HBc can be fractionated into IgM and IgG components. This is extremely helpful in differentiating between acute and past infections. Anti-HBc (IgM) rises during clinical hepatitis, persists for 2 to 8 months, and then declines, whereas anti-HBc (IgG) rises at the same time to a much higher level and persists for a long time. The detection of anti-HBc (IgM) indicates an acute infection, whereas if only anti-HBc (IgG) is present, the illness must be of at least 6 months' duration. Anti-HBc may be the only test that is positive in some individuals during the window period when HBsAg has become negative and before anti-HBs has become positive.
  3. Hepatitis e antigen (HBeAg): HBeAg is closely associated with the nucleocapsid of HBV. It is usually seen during the incubation phase and correlates with increased viral replication. Persistence of HBeAg beyond 10 to 12 weeks is probably indicative of progression to a chronic carrier state. Persistent presence of HBeAg indicates the following:
  • Presence of active viral replication.
  • Development of chronic active hepatitis.
  • Patient is highly infectious. The risk of infectivity in an individual who is positive for HBeAg and HBsAg may be as high as 30,000 times the risk in an individual with only HBsAg positivity. Approximately 10% to 15% of long-term carriers who are HBeAg positive convert each year to negative with the development of anti-HBe titers. These individuals are generally less contagious and have less active liver disease. Conversely, an individual can have reactivation of the disease, especially with immunosuppression, so that anti-HBe titers become negative and HBeAg becomes positive.
  1. Anti-hepatitis B e antigen (anti-HBe): This antibody appears with the disappearance of HBeAg and suggests resolving or reduced viral replication. It usually indicates a lower state of infectivity.
  2. Hepatitis C
  3. Serological tests for hepatitis C include antibody screening tests and confirmatory tests that measure HCV RNA.
  4. Enzyme immunoassay (EIA) detects antibodies to HCV (anti-HCV). The third-generation EIA test has enhanced sensitivity and a specificity > 99% in immunocompetent patients. A negative EIA excludes chronic HCV in patients with normal immune systems. Antibodies against HCV may not be found in the acute illness phase, in patients on hemodialysis, and in those who are profoundly immunodeficient. Conversely, patients with autoimmune diseases may show false-positive results. The EIA test should be followed by a qualitative RNA test to confirm the diagnosis of HCV infection.
  5. Direct measurement of viral RNA in serum remains the “gold standard” in the diagnosis of HCV infection. Qualitative and quantitative tests are available. The qualitative test is used to confirm the diagnosis of hepatitis C infection whereas the quantitative test is used to monitor the effectiveness of therapy.
  6. Delta hepatitis
  7. Delta antigen: Detectable in 20% of cases with acute delta infection.
  8. Delta antibody (anti-HDV): Both IgM and IgG antibodies can be measured.
  9. HDV RNA can be measured by polymerase chain reaction (PCR).
  10. Laboratory diagnosis in acute infection is based on serological tests for anti-HDV IgM or HDV RNA or delta virus antigen (HDVAg) in serum. In chronic infection, total (IgM + IgG) antibody is elevated with or without presence of HDVAg in the serum. High titers of IgG antibody suggest active replication. Detection of HDVAg by immunohistochemical analysis of liver tissue is considered the gold standard for diagnosis of persistent HDV infection.

Course

  1. Viral hepatitis A: The clinical course is summarized in Figure 30.2.
  2. More than 75% of adults and adolescents are symptomatic, while in children <3 years of age it is asymptomatic >80% of the time.
  3. Ninety-five percent of patients have a 4- to 6-week course.
  4. Stool isolates for HAV are the first positive finding.
  5. As IgM antibodies and liver enzymes rise, clinical symptoms appear.
  6. As clinical symptoms disappear and IgM antibodies fall, IgG antibodies rise.
  7. Rarely, individuals can have a relapsing course lasting up to 1 year, which can cause confusion with other causes of chronic liver disease. Also, autoimmune hepatitis can be a rare sequel to hepatitis A.
  8. Viral hepatitis B: The clinical course of a typical case is summarized in Figure 30.3.
  9. HBsAg and HBeAg titers rise 4 to 8 weeks after exposure and 4 to 8 weeks before clinical symptoms appear.
  10. Liver transaminases rise, and clinical symptoms appear.
  11. HBsAg may peak and fall in uncomplicated cases or remain positive in long-term carriers.
  12. Anti-HBc titers rise as HBsAg titers fall.
  13. Anti-HBs appears weeks to months after HBsAg disappears.
  14. A “window phase” may exist in which HBsAg is negative before anti-HBs appears. During this phase, anti-HBc IgM will be positive.
  15. Acute phase: After HBV infection the likelihood of developing acute hepatitis is age dependent. Perinatal HBV infection is almost always asymptomatic, whereas 5% to 15% of children 1 to 5 years of age and 33% to 50% of older children, adolescents, and adults develop acute hepatitis after HBV infection.
  16. Chronic HBV infection: Chronic HBV infection is defined as either the presence of HBsAg in serum for at least 6 months or the presence of HBsAg in a person who tests negative for anti-HBc IgM. The likelihood that a newly infected person will develop chronic HBV infection is also dependent on the age at the time of infection.
  • Ninety percent of adolescent and adult patients with hepatitis B recover without sequelae including chronic infections. However, >90% of infected infants, and 25% to 50% of younger children infected

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between 1 and 5 years of age develop chronic infection.

  • Hepatocellular carcinoma (HCC): Adults who have had chronic HBV infection since childhood develop HCC at a rate of 5% per decade. Up to 25% of infants and older children who acquire HBV infection eventually develop HBV-related HCC or cirrhosis.
  1. Hepatitis C
  2. The clinical course varies from asymptomatic infection (up to 70%) to icteric hepatitis (25%) to fulminant liver failure (rare).
  3. Antibody test results remain negative for several weeks after onset of disease.
  4. Chronic disease develops in approximately 55% to 85% of patients, unrelated to mode of transmission or clinical presentation.
  5. Ten percent to 25% of patients with chronic disease develop cirrhosis.
  6. Once cirrhosis develops, HCC develops at a rate of 2% per year.
  7. Delta hepatitis At least three clinical pictures can occur:
  8. Coinfection: Acute hepatitis caused by a combination of both HDV and HBV—often leading to a more severe form of acute hepatitis than that caused by HBV alone.
  9. Superinfection: Acute hepatitis with HDV acquisition in a long-term carrier of HBV. This may cause a second episode of clinical hepatitis and accelerate the course of the chronic liver disease, or cause overt disease in asymptomatic HBsAg carriers.
  10. Chronic infection: Chronic infection with both HDV and HBV, leading to a more rapid progression in liver disease and a higher mortality rate.

TABLE 30.3
Infectivity for Acute Hepatitis B Virus

HBsAg

Anti-HBc

HBeAg

Anti-HBe

Infectivity

Anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis B e antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.

+

+

+

-

Acute infection or chronic carrier; very infectious

+

+

-

-

Acute or recent infection; possible chronic carrier state; moderately infectious

+

+

-

+

Recent infection or chronic carrier state; good prognosis; probably low infectivity

Differential Diagnosis

  1. Drug-induced hepatitis
  2. Alcoholic hepatitis
  3. Toxic hepatitis
  4. Nonalcoholic steatohepatitis (NASH)
  5. Viral hepatitis
  6. Hepatitis A
  7. Hepatitis B (with or without delta coinfection or superinfection)
  8. Hepatitis C
  9. Hepatitis E
  10. Herpes simplex
  11. Cytomegalovirus infection
  12. Epstein-Barr virus infection
  13. Varicella
  14. Enteroviral (Coxsackie B and ECHO virus) infections
  15. Rubella
  16. Adenoviral infection

Diagnosis

  1. What causes acute hepatitis?
  2. Clinical history may suggest toxin, drug, or risk factors for hepatitis A, B, or C.
  3. Order IgM anti-HAV, HBsAg, anti-HBc IgM, anti-HCV EIA, and a mononucleosis spot test. Table 30.2 provides an interpretation of results from the first three of these tests. If hepatitis C is suspected as a cause of acute hepatitis, a qualitative RNA test will be needed as there is high likelihood of a false-negative EIA in this scenario.
  4. Acute hepatitis B: What is the infectivity of the patient? Table 30.3 summarizes the infectivity risk of HBV.

Therapy

General Measures

  1. Restriction of physical activity is not needed and teenagers with acute viral hepatitis can be as active as tolerated.
  2. Diet: There is no evidence that any special diet affects the course of the disease.
  3. Adolescents should avoid alcoholic beverages until transaminases return to normal.
  4. Adolescents should avoid oral contraceptives, steroids, and all hepatotoxic drugs.
  5. Severe disease is indicated by the following findings:
  6. Elevated prothrombin time
  7. Albumin <2.5 g/dL
  8. Evidence of ascites, edema, or encephalopathy
  9. Most cases of hepatitis in adolescents can be managed at home. If hydration cannot be maintained in the outpatient because of nausea and vomiting, hospitalization should be considered. If the home environment is not supportive or the disease activity is particularly severe (see previous discussion), hospitalization may be indicated.

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  1. When the prothrombin time is elevated, it needs to be followed up closely and the patient may need to be hospitalized. If the prothrombin time is normal or once it returns to normal, the concentrations of serum bilirubin and transaminases should be monitored weekly during the acute illness, then every 2 to 3 weeks as the teen improves and enzymes fall. Monitoring can be stopped when liver enzymes return to normal.

Chronic Hepatitis

Treatment of chronic hepatitis is beyond the scope of this book. Therapy should be conducted by a specialist who is experienced in the treatment of chronic hepatitis.

  1. Agents for treatment of chronic hepatitis B
  2. Interferon-α (IFN-α ): Interferon treatment is successful in 33% of patients, with success being defined as loss of HBeAg. Interferon therapy has fairly severe side effects.
  3. Lamivudine: Lamivudine therapy can suppress HBV replication. It needs to be used long term and the incidence of viral resistance increases with increasing duration of therapy.
  4. Adefovir dipivoxil is a newer agent that is recommended for lamivudine-resistant HBV infection.
  5. Pegylated IFN α-2a is a recently approved medication for HBV treatment.
  6. Agents for treatment of chronic hepatitis C

Hepatitis C is treated with a combination of pegylated interferon and ribavirin. The dosages and length of treatment depend on the HCV genotype and response to treatment.

Complications

  1. Acute hepatitis
  2. Pancreatitis
  3. Myocarditis
  4. Atypical pneumonia
  5. Aplastic anemia
  6. Transverse myelitis
  7. Glomerulonephritis
  8. Arthritis
  9. Fulminant hepatitis
  10. Chronic carrier state (HBsAg positive for longer than 6 months)
  11. Chronic hepatitis
  12. Cirrhosis and its complications including:
  13. Chronic liver failure
  14. Hepatocellular carcinoma

Prevention

Disinfection

  1. Heat sterilization
  2. Boiling in water at 100°C for 10 minutes
  3. Steam autoclaving at 121°C and 15 lb/in3for 15 minutes
  4. Dry heat of 160°C for 2 hours
  5. Other presumed effective modalities
  6. Sodium hypochlorite 2.5% for 30 minutes
  7. Formalin 40% for 12 hours
  8. Glutaraldehyde 2% for 10 hours

Prophylaxis

Hepatitis A

Good hand hygiene is central to the prevention of hepatitis A when working in environments with possible exposure (e.g., day-care centers). Effective public water sanitation and food hygiene are also important.

Hepatitis A Prophylaxis

  1. Agents: Agents available for preexposure prophylaxis for hepatitis A include human immune serum globulin (HISG) and hepatitis A vaccine. Whenever postexposure prophylaxis is attempted, HISG should be used as there are limited data on the effectiveness of the vaccine alone under such conditions.
  2. HISG: HISG is a concentrated solution of antibodies prepared from pooled plasma. It is at least 85% effective in preventing hepatitis A when given intramuscularly within 2 weeks of exposure and also affords short-term protection against hepatitis A for international travelers. HISG should be given along with hepatitis A vaccine (at a separate anatomical site) for those with risk for further exposures to hepatitis A.
  3. Hepatitis A vaccine: Hepatitis A vaccines offer active immunization and therefore longer and more effective protection than that provided by HISG. Two vaccines are available, Havrix (SmithKline Beecham Biologicals, Research Triangle, NC) and Vaqta (Merck, Inc., White Station, NJ). Havrix is approved for children older than 2 years and Vaqta is approved for children older than 12 months. The vaccines are both inactivated and come in adult and pediatric formulations, with different dosages and administration schedules. Immunogenicity studies indicate that almost 100% of children, adolescents, and adults develop protective levels of antibody to HAV after completing the vaccine series. Estimates suggest that protective levels can last at least 20 years. The vaccine can be administered simultaneously with other vaccines and toxoids. However, if other vaccines are given simultaneously, they should be given at separate injection sites. In addition to the above vaccines Twinrix is also available, which includes both hepatitis A and hepatitis B vaccines in one. Using three doses of Twinrix produces similar seroprotection for hepatitis A and B as using vaccines for A and B separately. Recommended dosing is at 0, 1, and 6 months.
  4. Recommended dosing schedules are as follows:

HAVRIX

Age (yr)

Dose (ELISA units)

Volume (mL)

No. of Doses

Schedule (mo)

2–18

720

0.5

2

0, 6–12

>18

1,440

1.0

2

0, 6–12

VAQTA

Age (yr)

Dose (units)

Volume (mL)

No. of Doses

Schedule (mo)

1–18

25

0.5

2

0, 6–18

>18

50

1.0

2

0, 6–18

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TABLE 30.4
Persons Needing Hepatitis A Vaccine or Immune Globulin

Adapted from Craig AS, Schaffner W. Prevention of hepatitis A with the hepatitis A vaccine. N Engl J Med 2004;350:476.

Hepatitis A vaccine

Children at least 2 years of age living in a state (Alaska, Arizona, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, or Washington) or a county with a high rate of infection (≥20 cases per 100,000 population from 1987 through 1997)

Travelers at least 1 year of age to countries with high or intermediate rates of disease

Men who have sex with men

Users of illicit drugs, both injecting and noninjecting

Persons who have chronic liver disease

Persons who use clotting factor concentrates

Laboratory personnel who work with the hepatitis A virus

Military personnel

Day care attendees older than 1 yr

Immune globulin

Persons who will be traveling to countries with high or intermediate rates of disease within the next 2 wk

Children younger than 1 yr who will be traveling to countries with high rates of disease

People who need the vaccine but are allergic to it or do not wish to take it

For postexposure prophylaxis, within 14 d of exposure:

1.  Persons who have been exposed to food that was handled by someone with acute hepatitis A, who had either poor hygiene or diarrhea

2.  Persons exposed to a family member with acute hepatitis A

Persons are considered to be protected by 4 weeks after the initial dose of hepatitis A vaccine. For long-term protection, a second dose is needed 6 to 12 months later. For persons who will travel to high-risk areas <4 weeks after the initial vaccine dose, HISG should be administered simultaneously with the first dose of vaccine but at a different injection site. A single dose of HISG (0.02 mL/kg of body weight) provides effective protection against hepatitis A for up to 3 months.

Recommendations for who should be given HISG and hepatitis A vaccine are outlined in Table 30.4. Additional information about hepatitis A vaccine is available from the CDC's Hepatitis Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, telephone 1-404-371-5910 or 9+1-404-371-5460 or at the Web site www.cdc.gov/mmwr/preview/mmwrhtml/rr4812a1.htm.

Hepatitis B

Hepatitis B Preexposure Prophylaxis

  1. Agents: Two types of products are available for prophylaxis against hepatitis B. Hepatitis B vaccines provide active immunization against hepatitis B infection and are recommended for both preexposure and postexposure prophylaxis. Hepatitis B immune globulin (HBIG) provides temporary, passive protection and is indicated only in certain postexposure settings.
  2. HBIG: HBIG is prepared from plasma preselected to contain a high titer of anti-HBs. The plasma used has been both screened for human immunodeficiency virus (HIV) antibodies and treated to inactivate and eliminate HIV from the final product.
  3. Hepatitis B vaccine: There are two recombinant hepatitis B vaccines licensed in the United States: Recombivax-HB (Merck, Inc.) and Engerix-B (Smith-Kline Beecham).
  4. Indications: The strategy of preventing hepatitis B transmission in the United States by identifying and vaccinating persons who were in major risk groups for acquiring the infection did not succeed. So, starting in the late 1980s, a comprehensive strategy to eliminate transmission of HBV during infancy and childhood, as well as during adolescence and adulthood, was devised. This included the following steps:
  5. Prevention of perinatal HBV infection through routine HBsAg screening of all pregnant women and appropriate postexposure immunoprophylaxis of children born to HBsAg-positive women (1988; see “Considerations During Pregnancy” section)
  6. Routine immunization of infants (1992). Recommended schedules for immunoprophylaxis to prevent perinatal transmission of hepatitis B and for vaccination of newborns are listed in Tables 30.5, 30.6, and 30.7.
  7. Routine immunization of adolescents not previously immunized (1995).
  8. Routine immunization of all previously unvaccinated children 0 to 18 years of age (1999). Adolescents are at higher risk of infection because of their risky sexual behavior and drug use during this developmental period. Because adolescents and young adults are not easily identified with regard to high-risk behavior, universal immunization of all preadolescents, adolescents, and young adults—and in

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particular those living in areas where high-risk behavior is prevalent—is recommended. The appropriate dose for age should be used (Table 30.5) and the schedule of vaccination at 0, 1, and 6 months is preferred.

TABLE 30.5
Recommended Doses of Currently Licensed Hepatitis B Vaccines
a

 

Recombivax-HB

Engerix-B

Group

µg

mL

µg

mL

HBsAg, hepatitis B surface antigen; HBIG, hepatitis B immune globulin.

aBoth vaccines are routinely administered in a three-dose series. Engerix-B has also been licensed for a four-dose series administered at 0, 1, 2, and 12 mo.
b Special formulation.
c Two 1-mL doses administered at one site, in a four-dose schedule at 0, 1, 2, and 6 mo.
Adapted from American Academy of Pediatrics. Committee on Infectious Diseases. Red Book 2003. AAP, 2003:318.

Infants of HBsAg-negative mothers, children, and adolescents (<20 yr)

 5

0.5

10

0.5

Infants of HBsAg-positive mothers; (HBIG [0.5 mL] also recommended)

 5

0.5

10

0.5

Adults (>20 yr)

10

1.0

20

1.0

Dialysis patients and other immunocompromised persons

40

 1.0b

40

 2.0c

TABLE 30.6
Recommended Schedule of Hepatitis B Immunoprophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus Infection
a

Condition

Age of Infant

HBsAg, hepatitis B surface antigen.

a See Table 30.3 for appropriate vaccine dose.
b Hepatitis B immune globulin (HBIG) 0.5 mL administered intramuscularly at a site different from that used for vaccine.
c If four-dose schedule (Engerix-B) is used, the third dose is administered at 2 mo of age and the fourth dose at 12–18 mo.
d First dose for infant of HBsAg-positive mother (see Table 30.3).
e Infants of women who are HBsAg negative can be vaccinated at 2 mo.
From Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the immunization practices advisory committee (ACIP). MMWR Morb Mortal Wkly Rep 1991;40(RR-13):1.

Infant born to mother known to be HBsAg positivea

 

 First vaccine dose

Birth (within 12 hr)

 HBIGb

Birth (within 12 hr)

 Second dose

1–2 mo

 Third dose

6 moc

Infant born to mother not screened for HBsAgd

 

 First vaccine dose

Birth (within 12 hr)

 HBIGb

If mother is found to be HBsAg positive, administer dose to infant as soon as possible, not later than 1 wk after birth

 Second dose

1–2 moe

 Third dose

6 moc

  1. Immunogenicity and efficacy
  2. When given in a three-dose series, recombinant vaccines induce protective anti-HBs antibodies in >90% of healthy adults and in >95% of infants, children, and adolescents from birth through 19 years of age. The deltoid muscle is the recommended site for the vaccination in adults and adolescents, because immunogenicity of the vaccine for adults is substantially lower when injections are given in the buttock. Hemodialysis patients and other immunocompromised persons in general develop a poorer response to the vaccines than healthy individuals do, and they require a larger dose. The

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vaccine has been shown to be 80% to 95% effective in preventing infection or hepatitis among susceptible persons.

  1. Although protection during the first years is excellent, there is evidence that by 7 years 30% to 50% of individuals develop low levels of antibodies, and 10% to 15% have undetectable antibodies. However, protection against viremic infection and clinical disease appears to persist. Persons younger than 20 years seem to have a higher peak response and longer persistence of detectable levels of antibodies.

TABLE 30.7
Recommended Schedules of Hepatitis B Vaccination for Infants Born to HBsAg-Negative Mothers
a

Hepatitis B Vaccine

Age of Infant

HBsAg, Hepatitis B surface antigen.

a Hepatitis B vaccine can be administered simultaneously with diphtheria-tetanus-pertussis, Haemophilus influenza type conjugate, measles-mumps-rubella, and oral polio vaccines at the same visit.
b At least 1 mo should elapse between the two doses.
From Centers for Disease Control and Prevention. Recommended childhood immunization schedule—United States 1995.MMWR Morb Mortal Wkly Rep 1995;44(RR-5):1.

Dose 1

Birth (before hospital discharge)

Dose 2

1–4 mob

Dose 3

6–18 mo

TABLE 30.8
Persons Needing Hepatitis B Vaccine

All newborns, at birth

All children, aged 0–18 yr, who have not been vaccinated

Heterosexuals with >1 partner in the previous 6 mo or with any sexually transmitted infection

Clients and staff of institutions for the developmentally disabled

Homosexual and bisexual men Injecting drug users

Persons with jobs involving contact with human blood

Hemodialysis patients

Recipients of clotting factor concentrates

Household and sexual contacts of carriers

Adoptees from countries of high hepatitis B endemicity

Inmates of long-term correctional facilities

International travelers who plan to stay in an endemic area for >6mo

  1. Vaccine dosage and safety
  2. Adults and older children (Table 30.5): Primary vaccination includes three intramuscular doses of vaccine, with the second and third doses given 1 and 6 months after the first. Adults and adolescents should receive a full dose; children younger than 11 years should receive half of the full dose. For patients undergoing hemodialysis and for other immunosuppressed patients, higher doses or an increased number of doses is required. In addition, as noted previously, Twinrix (combined hepatitis A and B vaccine) is also available. Recommended dosing is at 0, 1, and 6 months.
  3. Data are not available on the safety of hepatitis vaccines for the developing fetus. However, because the vaccines contain only noninfectious HBsAg particles, there should be no risk to the fetus. Hence, pregnancy or lactation should not be considered a contraindication to the use of the vaccine.
  4. Side effects—17% of individuals experience soreness at the site. Fifteen percent experience mild systemic symptoms including fever, headache, fatigue, and nausea.
  5. Prevaccination serological screening: Screening for past infection is probably only cost-effective in groups with a prior high risk of infection (>20%), and only if the cost of testing is not prohibitive. For groups with a low expected prevalence, such as health professionals in their training years, screening is not cost-effective. For routine screening, either anti-HBc or anti-HBs should be used. Anti-HBs screening identifies those previously infected, except carriers. Anti-HBc screening identifies all previously infected persons, both carriers and noncarriers. Vaccination without prevaccination testing is the most cost-effective approach in preadolescents and adolescents.
  6. Postvaccination serology and revaccination
  7. Testing for immunity is not recommended routinely but is advised for individuals who are expected to have a suboptimal response, such as those who received the vaccine in the buttock, those older than 50 years, those with known HIV infection, and individuals whose subsequent management depends on knowing their immune status, such as patients and staff of dialysis units. When necessary, the testing should be done between 1 and 6 months after completion of the vaccine series.

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  1. Testing of infants born to HBsAg-positive mothers who received immunoprophylaxis should be performed 3 to 9 months after completion of the vaccination series.
  2. Revaccination in nonresponders produces adequate antibody in 15% to 25% after one additional dose and in 30% to 50% after three additional doses, when the primary vaccination was given in the deltoid muscle. If the primary vaccine was given in the buttock, revaccination in the arm induces adequate antibodies in >75%. Revaccination should be considered for nonresponders who received the vaccine in the deltoid muscle, and it is recommended for nonresponders who received the primary vaccine in the buttock.

Hepatitis B Postexposure Prophylaxis

Prophylactic treatment to prevent hepatitis B infection after exposure should be considered in the following situations:

TABLE 30.9
Recommendations for Hepatitis B Prophylaxis after Percutaneous Exposure to Blood That Contains (or Might Contain) HBsAg

 

Treatment When Source Is

Exposed Person

HBsAg-Positive

HBsAg-Negative

Unknown or Not Tested

HBsAg, hepatitis B surface antigen; HBIG, hepatitis B immune globulin; anti-HBs, antibody to HBsAg.
a Dose of HBIG, 0.06 mL/kg intramuscularly.
b Persons known NOT to have responded to a three-dose vaccine series and to reimmunization with three additional doses should be given two doses of HBIG (0.06 mL/kg), one dose as soon as possible after exposure and the second 1 mo later.
c Adequate anti-HBs is ≥10 mIU/mL.
d Evaluate for antibody response after the vaccine booster dose. For persons who received HBIG, anti-HBs testing should be done when passively acquired antibody from HBIG is no longer detectable (e.g., 4–6 mo); if they did not receive HBIG, anti-HBs testing should be done 1–2 mo after the vaccine booster dose. If anti-HBs is inadequate after the vaccine booster dose, two additional doses should be administered to complete a three-dose reimmunization series.
Modified from the Centers for Disease Control and Prevention. Immunization of health care workers: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Hospital Infection Control Committee (HICPAC). MMWR Morb Mortal Wkly Rep 1997;46(RR-18):22.

Unimmunized

Administer HBIGa 1 dose and initiate hepatitis B vaccine

Initiate hepatitis B vaccine series

Initiate hepatitis B vaccine series

Previously immunized

     

 Known responder

No treatment

No treatment

No treatment

 Known nonresponder

HBIG 2 doses or HBIG 1 dose and initiate immunizationb

No treatment

If known high-risk source, treat as if source were HBsAg positive

 Response unknown

Test exposed person for anti-HBsc

No treatment

Test exposed person for anti-HBsc

 

1.  If adequate, HBIG 1 dose and vaccine booster dosed

2.  If adequate, no treatment

 

1.  If inadequate, vaccine booster dosea

2.  If adequate, no treatment

  1. Perinatal exposure of an infant born to an HBsAg-positive mother: A regimen that combines one dose of HBIG at birth with the hepatitis B vaccine series started soon after birth is 85% to 95% effective. (See “Considerations during Pregnancy” section.)
  2. Persons with acute exposure to blood: Decision on prophylaxis depends on whether the source of the blood is available, the hepatitis status of the exposed person, and the status of the source. After such an exposure, a blood sample should be obtained from the person who was the source of the exposure and tested for HBsAg. For greatest effectiveness, passive prophylaxis with HBIG, when indicated, should be given as soon as possible after exposure (the value beyond 7 days after exposure is unclear). A summary of recommendations is given in Table 30.9. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis can also be obtained at: http://www.cdc.gov/mmwr/PDF/rr/rr5011.pdf.
  3. Sexual contacts of HBsAg-positive persons: These individuals are at increased risk of infection, and HBIG is 75% effective in preventing such infections. Screening of sexual partners for hepatitis antibodies (anti-HBc or anti-HBs) before treatment is recommended but should not delay treatment beyond 14 days after last exposure.

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Treatment consists of HBIG (0.06 mL/kg), followed by the hepatitis vaccine series, which may be started at the same time if exposure continues.

  1. Household contacts of persons with acute infection: Prophylaxis is not indicated unless there is exposure to blood of the index case (e.g., sharing of toothbrushes or razors). If indicated, treatment is with both HBIG and vaccine. If the index patient becomes a carrier, all household contacts should receive hepatitis B vaccine. Treatment with HBIG and hepatitis B vaccine is also indicated for infants younger than 12 months whose primary caregivers have an acute hepatitis B infection.

Delta Hepatitis

Because HDV is dependent on HBV for replication, prevention of HBV infection suffices to prevent delta hepatitis. Exposures of individuals with known positivity for both HDV and HBV should be treated exactly as such exposures to HBV alone.

Hepatitis C

Immune globulin is not recommended for postexposure prophylaxis of hepatitis C.

Hygiene

Recommended guidelines include the following:

  1. No sharing of razors, toothbrushes, food utensils, or towels.
  2. Careful personal hygiene; hand washing after patient contact.
  3. Careful handling of secretions of the hepatitis B patient, including saliva, blood, and urine, with needle precautions.
  4. Hepatitis A: Isolate the patient until jaundice peaks; use stool precautions.

Considerations During Pregnancy

  1. Hepatitis A
  2. There is no maternal–fetal transmission.
  3. Transmission can occur during delivery.
  4. Positive IgM antibodies in the infant indicate acute infection.
  5. Hepatitis B
  6. Transmission of HBV from mother to infant during the perinatal period is one of the most efficient modes of hepatitis B infection. This often leads to severe long-term sequelae.
  7. The transmission rate to infants from mothers who are positive for both HBsAg and HBeAg is 70% to 90%, and 85% to 90% of infected infants become chronic hepatitis B carriers.
  8. Infants born to mothers who are HBsAg positive and HBeAg negative have 10% risk of acquiring perinatal infection.
  9. Prenatal screening of all pregnant women identifies those who are HBsAg positive and allows treatment of their newborns with HBIG and hepatitis B vaccine, which prevents development of the chronic carrier state in 90% to 95% of these infants. The Advisory Committee on Immunization Practices (Centers for Disease Control and Prevention, 1991and CDC, 2005) advises the following:
  • All pregnant women should be routinely tested for HBsAg during the first prenatal visit in each pregnancy. If the mother has a particularly high-risk behavior, an additional HBsAg test can be ordered later in the pregnancy. No other serological tests are necessary for maternal screening.
  • If the woman was not screened prenatally, HBsAg testing should be done at the time of admission for delivery. If the mother is identified as HBsAg positive 1 month or more after giving birth, the infant should be tested for HBsAg. If the infant is HBsAg negative, he/she should be given HBIG and hepatitis B vaccine.
  • When HBsAg testing of pregnant women is not feasible (i.e., in remote areas without access to a laboratory), all infants should receive hepatitis B vaccine <12 hours of birth and should complete the hepatitis B vaccine series according to a recommended schedule for infants born to HBsAg-positive mothers.
  • Infants born to HBsAg-positive mothers should receive HBIG (0.5 mL) intramuscularly once they are physiologically stable, preferably within 12 hours of birth. Hepatitis B vaccine should be administered intramuscularly at the appropriate infant dose. The first dose should be given concurrently with HBIG but at a different site. Subsequent doses should be given as recommended for the specific vaccine (Tables 30.5 and 30.6). Testing of infants for HBsAg and anti-HBs is recommended when they are 9 to 15 months of age to monitor the success or failure of therapy. If HBsAg is not detectable and anti-HBs is present, the child can be considered protected. HBIG and hepatitis B vaccination do not interfere with routine childhood vaccinations.
  • Obstetric and pediatric staff should be notified directly about HBsAg-positive mothers so that the neonates can receive therapy without delay.
  • Breast-feeding can be allowed even before the first dose of HBIG and can continue following immunizations. The mother should ensure that her nipples do not get traumatized.
  • Household members and sexual partners of HBV carriers should be tested, and, if susceptible, should receive hepatitis B vaccine.
  1. Hepatitis C
  2. An anti-HCV EIA should be performed at the first prenatal visit for pregnant women at high risk for exposure. HCV RNA testing should be performed if anti-HCV is positive. Women at high risk include those with a history of injection drug use, repeated exposure to blood products, prior blood transfusion, or organ transplantations.
  3. The rate of mother-to-infant transmission is 4% to 7% per pregnancy in women with HCV viremia. Coinfection with HIV increases the rate of transmission 4- to 5-fold. The actual time and mode of transmission are not known.
  4. Breast-feeding poses no important risk of HCV transmission if nipples are not traumatized and maternal hepatitis C is quiescent.
  5. Infants of mothers with hepatitis C should be tested for HCV RNA on two occasions, between the ages of 2 and 6 months and again at 18 to 24 months, along with serum anti-HCV.

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Web Sites

For Teenagers and Parents

http://www.cdc.gov/ncidod/diseases/hepatitis/. CDC hepatitis resource page.

http://www.liverfoundation.org. Numerous informational pieces from American Liver Foundation.

http://www.niddk.nih.gov/health/digest/pubs/hep/hepa/hepa.htm. What I Need to Know About Hepatitis A from National Institute of Diabetes and Digestive and Kidney Disease.

http://www.hepnet.com. Canadian hepatitis information network.

For Teens

http://www.nfid.org/factsheets/hbagadol.html. Hepatitis B: What Every Teen Should Know—National Foundation for Infectious Diseases.

http://www.kidshealth.org/teen/infections/stds/hepatitis.html. How Hepatitis Can Hurt You—The Nemours Foundation.

For Health Professionals

http://www.nlm.nih.gov/medlineplus/. Thirty five sites and links to MedLine, National Library of Medicine.

http://www.cdc.gov/ncidod/diseases/hepatitis/. CDC hepatitis resource page.

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Atkins M, Nolan M. Sexual transmission of hepatitis B. Curr Opin Infect Dis 2005;18:67.

Becherer PR. Viral hepatitis: what have we learned about risk factors and transmission? Postgrad Med 1995;98:65.

Belfeler AS, Di Besceglie AM. Hepatitis B. Infect Dis Clin North Am 2000;14:617.

Broderick A, Jonas MM. Management of hepatitis B in children. Clin Liver Dis 2004;8:387.

Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the immunization practices advisory committee (ACIP). MMWR Morb Mortal Wkly Rep 1991;40(RR-13):1.

Centers for Disease Control and Prevention. Licensure of inactivated hepatitis A vaccine and recommendations for use among international travelers. MMWR Morb Mortal Wkly Rep 1995;44:559.

Centers for Disease Control and Prevention. Update: recommendations to prevent hepatitis B virus transmission–United States. JAMA 1995;274:603.

Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus infection and HCV-related chronic disease. MMWR Morb Mortal Wkly Rep 1998;47(RR-19):1.

Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization. MMWR Morb Mortal Wkly Rep 1999;48(RR-12):1.

Centers for Disease Control and Prevention. Notice to readers: alternate two-dose hepatitis B vaccination schedule for adolescents aged 11–15 Years. MMWR Morb Mortal Wkly Rep 2000;49:261.

Centers for Disease Control and Prevention. Acute hepatitis B among children and adolescents—United States, 1990–2002. MMWR Morb Mortal Wkly Rep 2004;53:1015.

Centers for Disease Control and Prevention: A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus Infection in the United States. MMWR Morb Mortal Wkly Rep 2005;54:1.

Clemens R, Safary A, Hepburn A, et al. Clinical experience with an inactivated hepatitis A vaccine. J Infect Dis 1995;171(Suppl 1):S44.

Craig AS, Schaffner W. Prevention of hepatitis A with the hepatitis A vaccine. N Engl J Med 2004;350:476.

Cuthbert JA. Hepatitis A: old and new. Clin Microbiol Rev 2001;14:38.

Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256.

Fung SK, Lok AS. Update on viral hepatitis in 2004. Curr Opin Gastroenterol 2005;21:300.

Ganiats TG. Hepatitis B immunization for adolescents. West J Med 1995;163:70.

Gershon AA. Present and future challenges of immunizations on the health of our patients. Pediatr Infect Dis J 1995;14:445.

Gibb DM, Goodall RL, Dunn DT, et al. Mother-to-child transmission of hepatitis C virus: evidence for preventable prepartum transmission. Lancet 2000;356:904.

Goldberg D, Anderson E. Hepatitis C: who is at risk and how do we identify them? J Viral Hepat 2004;11(Suppl 1):12.

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Hess G. Virological and serological aspects of hepatitis B and the delta agent. Gut 1993;34:51.

Hill L, Henry B, Schweikert S. Prevention Practice Committee, American College of Preventive Medicine. Screening for chronic hepatitis C: American College of Preventive Medicine practice policy statement. Am J Prev Med 2005;28:327.

Karayiannis P, Main J, Thomas HC. Hepatitis vaccines. Br Med Bull 2004;70:29.

Kemmer NM, Miskovsky EP. Hepatitis A. Infect Dis Clin North Am 2000;14:605.

Kew M, Francois G, Lavanchy D, et al. Prevention of hepatitis C virus infection. J Viral Hepat 2004;11:198.

Kwan-Gett TS, Whitaker RC, Kempter KJ. A cost-effectiveness analysis of prevaccination testing for hepatitis B in adolescents and preadolescents. Arch Pediatr Adolesc Med1994;148:915.

Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11:97.

Leach CT. Hepatitis A in the United States. Pediatr Infect Dis J 2004;23:551.

Mondelli MU, Cerino A, Cividini A. Acute hepatitis C: diagnosis and management. J Hepatol 2005;42(Suppl 1):S108.

Niro GA, Rosina F, Rizzetto M. Treatment of hepatitis D. J Viral Hepat 2005;12:2.

Pearlman BL. Hepatitis C infection: a clinical review. South Med J 2004;97:364.

Petermann S, Ernest JM. Intrapartum hepatitis B screening. Am J Obstet Gynecol 1995;173:369.

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Schwarz KB, Balistreri W. Viral hepatitis. J Pediatr Gastroenterol Nutr 2002;35(Suppl 1):S29.

Shepard CW, Finelli L, Fiore AE, et al. Epidemiology of hepatitis B and hepatitis B virus infection in United States children. Pediatr Infect Dis J 2005;24:755.

Shukla NB, Poles MA. Hepatitis B virus infection: co-infection with hepatitis C virus, hepatitis D virus, and human immunodeficiency virus. Clin Liver Dis 2004;8:445.

Thomson EC, Main J. Advances in hepatitis B and C. Curr Opin Infect Dis 2004;17:449.

Tovo PA, Lazier L, Versace A. Hepatitis B virus and hepatitis C virus infections in children. Curr Opin Infect Dis 2005;18:261.

Trepo C, Zoulim F, Alonso C, et al. Diagnostic markers of viral hepatitis B and C. Gut 1993;34:S20.

Wagner G, Lavanchy D, Darioli R, et al. Simultaneous active and passive immunization against hepatitis A studied in a population of travelers. Vaccine 1993;11:1027.

Weinstock HS, Bolan G, Moran JS, et al. Routine hepatitis B vaccination in a clinic for sexually transmitted diseases. Am J Public Health 1995;85:846.