A. Viral Characteristics

1. Picornavirus Family: enteric linear single-stranded RNA virus
   1. 28nm icosahedral particle
   2. Single positive strand 7.5kb RNA
   3. Singe open reading frame of 6.7kb
   4. RNA directed RNA polymerase
   5. Four viral capsid structural proteins (VP1-4)
   6. Seven nonstructural proteins
   7. Viral proteinase 3C cuts polypeptide to mature structural / non-structural proteins
   8. Viral replication restricted to hepatocyte cytoplasm
   9. Viral receptor unknown
   10. Single serotype and 4 genotypes
2. Transmission [3]
   1. Contaminated food (usually raw shellfish) or water
   2. Person to person via the fecal to oral route
   3. Found in feces ~3-4 weeks after exposure
   4. Highest transmission in areas of poor sanitation and hygiene
   5. Virus is highly resistant to bile acids and intestinal enzymes
3. Scope of Disease [4]
   1. ~100,000 cases acute hepatitis per year in USA (~100 deaths)
   2. >90% of cases are self limited
   3. In USA, causes ~50% of clinically important hepatitis
   4. In developing countries, ~100% of population is exposed and has antibodies
4. HAV infection is restricted to the liver
5. Excreted into bile and passed unharmed through intestine, excreted with feces

B. HAV Disease [4]

1. Incubation period up to 50 days, average is ~3-4 weeks
2. Symptoms peak 4-5 weeks
   1. Prodrome initially, flulike illness including malaise, fatigue, fever
   2. Abdominal pain, slight liver enlargement
   3. Nausea, vomiting, anorexia
   4. Jaundice with mild pruritus, dark urine usualy precedes the jaundice
3. Clinical Syndromes
   1. Self limited acute hepatitis (full resolution in <3 months), >90%
   2. Fulminant progressive hepatitis and liver failure, <1% of cases
   3. Cholestatic hepatitis - very uncommon, may respond to glucocorticoids
   4. Relapsing hepatitis - weeks to months after initial self-limited course
4. Laboratory
   1. IgM Abs (anti-HAV) begin 4-5 weeks
   2. IgG Abs indicative of previous infection
   3. Elevated transaminases in 500-5000 U/L range
   4. Elevated bilirubin levels (often >10mg/dL)
   5. Monitor PT and PTT closely for liver synthetic function
   6. PT prolongation >3 seconds is considered severe coagulopathy
5. Severe Disease
   1. Fulminant hepatic failure ~2% (higher risk in elderly)
   2. Death 1-2%
6. Complete recovery in 85% of persons by 3 months

C. Treatment

1. No specific therapy
2. Post-Exposure Prophylaxis [5]
   1. HAV immune globulin prevents ~85% of disease when given within 2 weeks of exposure
   2. Generally well tolerated (0.02mL/kg given intramuscularly)
   3. HAV vaccine may also be effective when given within 2 weeks of exposure (see below)
   4. In direct comparison, HAV vaccine had 4.4% cases versus 3.3% with immune globulin in a post-exposure prophylaxis situation; results not statistically significant [5]
   5. Either prevention method may be used, and HAV vaccine provides longer lasting immunity
3. Supportive therapy
   1. Intravenous fluids may be required
   2. Reversal of coagulopathy - vitamin K, coagulation factors as needed
   3. Hepatitis A immune globulin - for prevention of disease in patient contacts
4. Fulminant failure may require transplantation

D. Prevention [2,6]

1. FDA approved inactivated HAV vaccines [7]
   1. Havrix® - adults 1mL and children 0.5mL, 2 doses 6-12 months apart
   2. Vaqta® - same as Havrix®
   3. Twinrix® - combination HAV+HBV, FDA approved for adults only, 0, 1, 6 months
   4. Immunity after 2 dose vaccine likely lasts at least 10 years
   5. Combination vaccine appears effective in children 1-15 years as well
2. All persons at risk for contracting HAV should be vaccinated [2]
   1. Children living in communities with high HAV rates
   2. All children living in Alaska, Arizona, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, Washington and 6 other states
   3. Probably should be given to ALL children in USA [2,12]
   4. International travelers age at least 2 years to regions of endemic disease
   5. Homosexual men with multiple sex partners
   6. Injection drug abusers (IVDA)
   7. People with chronic liver disease [8] or patients with liver transplant
   8. People exposed to non-human primates
   9. Staffs of chronic health care and intensive care facilities
   10. Persons using clotting factor concentrates
   11. Food Handlers
3. Efficacy of Inactivated Virus Vaccine [7]
   1. 96% of recipients have high antibody titers in 30 days
   2. About 80% effective in prevention of secondary HAV infection (household contacts) [9]
   3. Vaccinating children in an endemic area prevents disease and outbreaks and is safe [10]
   4. HAV vaccination in children lead to reduction in disease rates ~75% [11]
   5. Universal vaccination of all toddlers in Israel lead to disease reduction of 95% [12]
4. HAV Immune Globulin [5]
   1. Should be given to anyone at risk who has no circulating anti-HAV antibodies
   2. Need not be given if person was vaccinated at least one month before contact
   3. Any person going to country with high or intermediate rates of disease within 2 weeks
   4. Children <2 years traveling to countries with high rates of disease
   5. May be given within 2 weeks after exposure to HAV (~85% effective)
   6. HAV vaccine about as effective as HAV immune globulin for post-exposure prophylaxis [5]
   7. Should be given to nonimmune close contacts of persons with clinical HAV infection [2]
   8. Avoid in all patients with IgA deficiency
   9. Generally well tolerated
   10. May be used for short term (1-2 month) protection (0.02mL/kg)

References

1. Koff RS. 1998. Lancet. 351(9116):1643
2. Craig AS and Schaffner W. 2004. NEJM. 350(5):476
3. Acheson DWK and Fiore AE. 2004. NEJM. 350(5):437
4. Willner IR, Uhl MD, Howard SC, et al. 1998. Ann Intern Med. 128(2):111
5. Victor JC, Monto AS, Surdina TY, et al. 2007. NEJM. 357(17):1685
6. Levy MJ, Herrera JL, DiPalma JA. 1998. Am J Med. 105(5):416
7. HAV Vaccines. 1995. Med Let. 37(950):51
8. Keeffe EB, Iwarson S, McMahon BJ, et al. 1998. Hepatology. 27:881
9. Sagliocca L, Amoroso P, Stroffolini T, et al. 1999. Lancet. 353(9159):1136
10. Averhoff F, Shapiro CN, Bell BP, et al. 2001. JAMA. 286(23):2968
11. Wasley A, Samandari T, Bell BP. 2005. JAMA. 294(2):194
12. Dagan R, Levnthal A, Anis E, et al. 2005. JAMA. 294(2):202