Learning Your “A B C s”

1. Learning Your “A B C s” The Hepatitis Viruses Jayesh A. Patel, MD, DTM&H

2. Conflicts of Interest No financial or other conflicts of interest for this talk.

3. Hepatitis causing Viruses Acute hepatitis may occur as part of the clinical course of a number of viral infections, including Human Cytomegalovirus, Epstein-Barr virus, Herpes Simplex Virus, Yellow Fever Virus and Rubella. The term "hepatitis virus" is usually used to describe infections caused by agents whose primary tissue tropism is the liver. At least five hepatitis viruses have been recognized and these have been named, hepatitis A, B, C, D and E.

5. Clinical Features Hepatitis due to all these viruses presents clinically in a very similar fashion, especially during the acute phase. Thus, a specific diagnosis can only be made in the laboratory. The majority of infections are often asymptomatic or produce only mild non-specific symptoms. Common clinical features include: anorexia, nausea, vomiting, right upper quadrant pain and raised liver enzymes AST and ALT. Jaundice is the hall mark of infection, but tends to develop late. Anicteric cases are also very common.

6. Hepatitis A Family: PicornaviridaeStructure: small; 27 nm in diameter, non-enveloped spherical particle

7. Hepatitis A: Key Facts Hepatitis A can cause mild to severe illness. Globally, there are an estimated 1.4 million cases of hepatitis A every year. The hepatitis A virus is transmitted through ingestion of contaminated food and water, or through direct contact with an infectious person. Hepatitis A is associated with a lack of safe water and poor sanitation.

8. Hepatitis A: Key Facts Epidemics can be explosive in growth and cause significant economic losses. Improved sanitation and the hepatitis A vaccine are the most effective ways to combat the disease. Hepatitis A rates in the United States have declined by 95% since Hepatitis A vaccine first became available in 1995. In 2010, 1,670 acute symptomatic cases of Hepatitis A were reported. After adjusting for asymptomatic infection and underreporting, the estimated number of new infections was 17,000

9. Hepatitis A: Clinical Features Incubation period 2-7 weeks (mean 28 days) Symptoms of hepatitis A range from mild to severe, and can include fever, malaise, loss of appetite, diarrhea, nausea, abdominal discomfort, dark-colored urine and jaundice  Pre-ictericphase lasting about 5 days. The subsequent icteric phase resolves within 3 months in 85% of cases.

10. Hepatitis A: Clinical Features Convalescence may be prolonged, and fatigue and alcohol intolerance can last up to 18 months. There is no chronic form of the disease. Milder disease than Hepatitis B; asymptomatic infections are very common, especially in children. Adults, especially pregnant women, may develop more severe disease. Fulminant hepatitis: rare; 0.3-1.8 % of casesHighest risk: pregnant women, elderly, pre-existing liver disease, other chronic medical conditions

11. Hepatitis A: Pathogenesis Virus enters via the gut; replicates in the alimentary tract and spreads to infect the liver, where it multiplies in hepatocytes. Viremiais transient. Virus is excreted in the stools for two weeks preceding the onset of symptoms.

12. Hepatitis A: Epidemiology

13. Hepatitis A: Diagnosis Virus cannot be cultured in vitro from clinical material; diagnosis depends on:Serology HAV-specific IgM

14. What does the Hepatitis A test result mean? If you have not been given the hepatitisvaccine, results of hepatitis testing indicates the following:

15. Hepatitis A

16. Hepatitis A Treatment There is no specific treatment for hepatitis A. Therapy is aimed at maintaining comfort and adequate nutritional balance, including replacement of fluids that are lost from vomiting and diarrhea.

17. Hepatitis A: Prevention Hygiene: Food hygiene, Hand hygiene Active ImmunizationInactivated cell culture derived vaccine is available; it is recommended for travelers to developing countries and, indeed, all adults who are not immune. It is the recommended form of post-exposure prophylaxis if the exposure is identified early, and if there are no predisposing risk factors for severe disease. If there are such risk factors, or if prophylaxis is delayed, passive immunization in addition to vaccination is recommended. Passive immunisationNormal immunoglobulin (antibody prepared from pooled human serum) given to close contacts of acute cases.Protection is short lived: three months

18. Hepatitis A Vaccines Havrix and Vaqta, Twinrix Hepatitis A vaccination is recommended for all children older than age 1. People who work or travel in areas where hepatitis A is common should be vaccinated. These areas include Africa, Asia (except Japan), the Mediterranean, Eastern Europe, the Middle East, Central and South America, Mexico, and parts of the Caribbean. If you are traveling to these areas before you are fully immunized (fewer than 4 weeks after your first shot), you should get a preventive dose of immunoglobulin (IG). If you are just a short-term traveler to these areas, you may wish to receive immunoglobulin (IG) instead of the vaccine.

19. Hepatitis A Vaccine • Other people who are at higher risk for hepatitis A include: • People who use recreational, injectable drugs • People who work with the hepatitis A virus in a laboratory or with primates that may be infected with the virus • People who have chronic liver disease • People who receive clotting factor concentrate to treat hemophilia or other clotting disorders • Military personnel • Men who have sex with other men • Employees of child day care centers • People who care for patients living in long-term nursing homes and other facilities

20. Hepatitis A Vaccines

21. Post-exposure Prophylaxis: Hepatitis A Persons who have recently been exposed to HAV and who have not been vaccinated previously should be administered a single dose of Hepatitis A vaccine or IG (0.02 mL/kg) as soon as possible, within 2 weeks after exposure. The guidelines vary by age and health status: For healthy persons aged 12 months–40 years, Hepatitis A vaccine at the age-appropriate dose is preferred to IG because of the vaccine’s advantages, including long-term protection and ease of administration, as well as the equivalent efficacy of vaccine to IG. For persons aged 40 years and older, IG is preferred because of the absence of information regarding vaccine performance in this age group and because of the more severe manifestations of Hepatitis A in older adults. The magnitude of the risk of HAV transmission from the exposure should be considered in decisions to use vaccine or IG in this age group.  Vaccine can be used if IG cannot be obtained. IG should be used for children aged less than12 months, immunocompromised persons, persons with chronic liver disease, and persons who are allergic to the vaccine

22. Which groups do NOT need routine vaccination against Hepatitis A? Food service workers.Consideration may be given to vaccination of employees who work in areas where community-wide outbreaks are occurring and where state and local health authorities or private employers determine that such vaccination is cost-effective. Health care workers.  If a patient with Hepatitis A is admitted to the hospital, routine infection-control precautions will prevent transmission to hospital staff. Children under 12 months of age. Because of the limited experience with Hepatitis A vaccination among children in this age group, the vaccine is not currently licensed for children age <12 months. Child care center attendees. The frequency of outbreaks of Hepatitis A is not high enough in this setting to warrant routine Hepatitis A vaccination of staff Residents of institutions for developmentally disabled persons. The occurrence of HAV infection has diminished, and routine vaccination against Hepatitis A is no longer recommended for this population.

23. Who requires protection (i.e., IG or Hepatitis A vaccine) after exposure to HAV? • Close personal contacts. Close personal contacts of persons with serologically confirmed Hepatitis A (i.e., through a blood test), including: • Household and sex contacts • Persons who have shared illicit drugs with someone with Hepatitis A • Consideration should also be given for other types of ongoing, close personal contact with a person with Hepatitis A (e.g., a regular babysitter or caretaker).

24. Who requires protection (i.e., IG or Hepatitis A vaccine) AFTER exposure to HAV? Child-care center staff, attendees, and attendees' household members PEP should be administered to all previously unvaccinated staff and attendees of child care centers or homes if 1) one or more cases of Hepatitis A are recognized in children or employees or 2) cases are recognized in two or more households of center attendees. In centers that provide care only to older children who no longer wear diapers, PEP need be administered only to classroom contacts of the index patient (i.e., not to children or staff in other classrooms). When an outbreak occurs (i.e., Hepatitis A cases in three or more families), PEP should also be considered for members of households that have diaper-wearing children attending the center.

25. If a case of Hepatitis A is found in a school, hospital, or office setting, what should be done? If a single case of Hepatitis A is identified in a school (other than a child care setting in which children wear diapers), office, or other work setting, and if the source of infection is outside the school or work setting, PEP (i.e., injection of IG or Hepatitis A vaccine) is not routinely recommended. Similarly, when a person who has Hepatitis A is admitted to a hospital, staff should not routinely be administered PEP; instead, careful hygienic practices should be emphasized. However, if it is determined that Hepatitis A has been spread among students in a school or among patients and staff in a hospital, PEP should be administered to unvaccinated persons who have had close contact with an infected person.

26. Hepatitis B: Key Facts Hepatitis B is a viral infection that can cause both acute and chronic disease. The virus is transmitted through contact with the blood or other body fluids of an infected person. About 240 million people are living with chronic hepatitis B and 600 000 people die every year due to the consequences of hepatitis B.(USA 1 mil./4000) Hepatitis B is an important occupational hazard for health workers. Hepatitis B is preventable with the currently available safe and effective vaccines.

27. Hepatitis B: Epidemiology In highly endemic areas, HBV is most commonly spread from mother to child at birth, or from person to person in early childhood. Perinatal or early childhood transmission may also account for more than one third of chronic infections in areas of low endemicity, although in those settings, sexual transmission and the use of contaminated needles, especially among injecting drug users, are the major routes of infection. The hepatitis B virus can survive outside the body for at least seven days. During this time, the virus can still cause infection if it enters the body of a person who is not protected by the vaccine. The hepatitis B virus is not spread by contaminated food or water, and cannot be spread casually in the workplace. The incubation period of the hepatitis B virus is 75 days on average, but can vary from 30 to 180 days. The virus may be detected 30 to 60 days after infection and persists for variable periods of time.

28. Hepatitis B Prevalence

31. Hepatitis B Serology Hepatitis B surface antigen (HBsAg): A protein on the surface of HBV; it can be detected in high levels in serum during acute or chronic HBV infection. The presence of HBsAg indicates that the person is infectious. The body normally produces antibodies to HBsAg as part of the normal immune response to infection. HBsAg is the antigen used to make Hepatitis B vaccine. Hepatitis B surface antibody (anti-HBs): The presence of anti-HBs is generally interpreted as indicating recovery and immunity from HBV infection. Anti-HBs also develops in a person who has been successfully vaccinated against Hepatitis B.

32. Hepatitis B Serology IgM antibody to Hepatitis B core antigen (IgM anti-HBc): Positivity indicates recent infection with HBV (≤6 months). Its presence indicates acute infection. Total Hepatitis B core antibody (anti-HBc): Appears at the onset of symptoms in acute Hepatitis B and persists for life. The presence of anti-HBc indicates previous or ongoing infection with HBV in an undefined time frame.

33. Hepatitis B Serology Hepatitis B e antigen (HBeAg): A secreted product of the nucleocapsid gene of HBV that is found in serum during acute and chronic Hepatitis B. Its presence indicates that the virus is replicating and the infected person has high levels of HBV. Hepatitis B e antibody (HBeAb or anti-HBe): Produced by the immune system temporarily during acute HBV infection or consistently during or after a burst in viral replication. Spontaneous conversion from e antigen to e antibody (a change known as seroconversion) is a predictor of long-term clearance of HBV in patients undergoing antiviral therapy and indicates lower levels of HBV.

34. Hepatitis B Serology Interpretation -

35. Hepatitis B serology How long does it take for blood to test HBsAg-positive after exposure to HBV? HBsAg will be detected in an infected person’s blood an average of 4 weeks (range: 1–9 weeks) after exposure to the virus. About 1 of 2 patients will no longer be infectious by 7 weeks after onset of symptoms, and all patients who do not remain chronically infected will be HBsAg-negative by 15 weeks after onset of symptoms

36. Who should be vaccinated against Hepatitis B? All infants, beginning at birth All children aged <19 years who have not been vaccinated previously Susceptible sex partners of Hepatitis B surface antigen (HBsAg)-positive persons Sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., >1 sex partner during the previous 6 months) Persons seeking evaluation or treatment for a sexually transmitted disease Men who have sex with men Injection drug users Susceptible household contacts of HBsAg-positive persons

37. Who should be vaccinated against Hepatitis B? Health care and public safety workers at risk for exposure to blood or blood-contaminated body fluids Persons with end-stage renal disease, including predialysis, hemodialysis, peritoneal dialysis, and home dialysis patients Residents and staff of facilities for developmentally disabled persons Travelers to areas with high Hepatitis B endemicity Persons with chronic liver disease Persons with HIV infection Unvaccinated adults with diabetes mellitus who are aged 19 through 59 years (discretion of clinicians for unvaccinated adults with diabetes mellitus who are aged ≥60 years) All other persons seeking protection from HBV infection

38. What are the Hepatitis B vaccines licensed in the United States? Single-antigen Hepatitis B vaccines ENGERIX-B® RECOMBIVAX HB® Combination vaccines COMVAX®: Combined Hepatitis B-Haemophilusinfluenzae type b (Hib) conjugate vaccine. Cannot be administered before age 6 weeks or after age 71 months. PEDIARIX®: Combined Hepatitis B, diphtheria, tetanus, acellularpertussis (DTaP), and inactivated poliovirus (IPV) vaccine. Cannot be administered before age 6 weeks or after age 7 years. TWINRIX®: Combined Hepatitis A and Hepatitis B vaccine. recommended for persons aged ≥18 years who are at increased risk for both Hepatitis A virus and HBV infections.

39. Can a patient receive the first dose of Hepatitis B vaccine from one manufacturer and subsequent doses from another manufacturer? • Yes. No differences in immune response are observed when vaccines from different manufacturers are used to complete the vaccine series. • If there is an interruption between doses of Hepatitis B vaccine, does the vaccine series need to be restarted? • No, the series does not need to be restarted. If the vaccine series was interrupted after the first dose, the second dose should be administered as soon as possible. The second and third doses should be separated by an interval of at least 8 weeks. If only the third dose is delayed, it should be administered as soon as possible. • Is it harmful to administer an extra dose(s) of Hepatitis A or Hepatitis B vaccine or to repeat the entire vaccine series if documentation of vaccination history is unavailable? • No. If necessary, administering extra doses of Hepatitis A or Hepatitis B vaccine is not harmful.

40. Who should receive postvaccination testing? • Testing for immunity is advised only for persons whose subsequent clinical management depends on knowledge of their immune status, including • Infants born to HBsAg-positive mothers • Health care workers and public safety workers at high risk for continued percutaneous or mucosal exposure to blood or body fluids • Chronic hemodialysis patients, HIV-infected persons, and other immunocompromised persons (e.g., hematopoietic stem-cell transplant recipients or persons receiving chemotherapy) • Sex partners of persons with chronic HBV infection

41. Are booster doses of Hepatitis B vaccine recommended? • Booster doses are recommended only in certain circumstances: • For hemodialysis patients, the need for booster doses should be assessed by annual testing for antibody to Hepatitis B surface antigen (anti-HBs). A booster dose should be administered when anti-HBs levels decline to <10 mIU/mL. • For other immunocompromised persons (e.g., HIV-infected persons, hematopoietic stem-cell transplant recipients, and persons receiving chemotherapy), the need for booster doses has not been determined. When anti-HBs levels decline to <10 mIU/mL, annual anti-HBs testing and booster doses should be considered for those with an ongoing risk for exposure. • For persons with normal immune status who have been vaccinated, booster doses are not recommended.

42. Approved Hepatitis B Drugs Interferon Alpha (Intron A) is given by injection several times a week for six months to a year, or sometimes longer. Can cause side effects such as flu-like symptoms (mainly fever, headache, chills, myalgia, and fatigue). Injection site reaction. Rash, alopecia, anemia, neutropenia. Psychiatric side effects have included depression (up to 40%), anxiety (up to 9%), and nervousness (up to 3%). Abnormal dreaming, aggravated depression, aggressive reaction, apathy, emotional lability, feeling of ebriety, manic depression, manic reaction, personality disorder, psychosis, suicidal ideation, and suicide attempt have been reported in less than 5% of patients. Frontal subcortical dementia and choreic movements mimicking Huntington's disease have been reported. Homicidal ideation and psychosis including hallucinations have been reported. Pegylated Interferon (Pegasys) is given by injection once a week usually for six months to a year. Same side effects as Interferon alpha but less often, less sever.

43. Approved Hepatitis B Drugs Lamivudine (Epivir-HBV, Zeffix, or Heptodin) for at least one year or longer. Can cause  headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea, cough, lactic acidosis. AdefovirDipivoxil (Hepsera) for at least one year or longer. Can cause asthenia, headache, abdominal pain, nausea, flatulence, diarrhea, dyspepsia, elevated creatinine, hematuria, hypophosphatemia. Entecavir (Baraclude) for at least one year or longer. Can cause headache, fatigue, dizziness, and nausea. Telbivudine (Tyzeka, Sebivo) for at least one year or longer. Can cause chills, fever, diarrhea, runny nose, cough, lactic acidosis. Tenofovir (Viread) is a pill taken once a day, for at least one year or longer.  Can cause rash, diarrhea, headache, body pain, depression, asthenia, and nausea.

44. Hepatitis C Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States; approximately 3.2 million persons are chronically infected. It can range in severity from a mild illness lasting a few weeks to a serious, lifelong illness.

45. Hepatitis C Sixty to 70% of persons newly infected with HCV typically are usually asymptomatic or have a mild clinical illness. HCV RNA can be detected in blood within 1–3 weeks after exposure. The average time from exposure to antibody to HCV (anti-HCV) seroconversion is 8–9 weeks, and anti-HCV can be detected in >97% of persons by 6 months after exposure. Chronic HCV infection develops in 70%–85% of HCV-infected persons; 60%–70% of chronically infected persons have evidence of active liver disease. The majority of infected persons might not be aware of their infection because they are not clinically ill.

46. Hepatitis C HCV is most efficiently transmitted through percutaneous exposure to infected blood (e.g., through transfusion of blood from unscreened donors or through use of injecting drugs). Although much less frequent, occupational, perinatal, and sexual exposures also can result in transmission of HCV. Can HCV be spread within a household? Yes, but this does not occur very often. If HCV is spread within a household, it is most likely a result of direct, through-the-skin exposure to the blood of an infected household member.

47. Hepatitis C • What is the risk of acquiring HCV infection from transfused blood or blood products in the United States? • Now that more advanced screening tests for HCV are used in blood banks, the risk is considered to be less than 1 chance per 2 million units transfused. Before 1992, when blood screening for HCV became available, blood transfusion was a leading means of HCV transmission. • Can HCV be spread during medical or dental procedures? • As long as Standard Precautions and other infection control practices are used consistently, medical and dental procedures performed in the United States generally do not pose a risk for the spread of HCV. However, HCV has been spread in health care settings when injection equipment, such as syringes, was shared between patients or when injectable medications or intravenous solutions were mishandled and became contaminated with blood. Health care personnel should understand and adhere to Standard Precautions, which includes safe injection practices and other guidance aimed at reducing bloodborne pathogen risks for patients and health care personnel.

48. Hepatitis C What percentage of persons infected with HCV develop symptoms of acute illness? Approximately 20%–30% of those newly infected with HCV experience fatigue, abdominal pain, poor appetite, or jaundice. How soon after exposure to HCV do symptoms appear? In those persons who do develop symptoms, the average time period from exposure to symptom onset is 4–12 weeks (range: 2–24 weeks).

49. Hepatitis C and Health Care Personnel • What is the risk for HCV infection from a needlestick exposure to HCV-contaminated blood? • After a needlestick or sharps exposure to HCV-positive blood, the risk of HCV infection is approximately 1.8%. • Other than needlesticks, do other exposures, such as splashes to the eye, pose a risk to health care personnel for HCV transmission? • Although a few cases of HCV transmission via blood splash to the eye have been reported, the risk for such transmission is expected to be very low. Avoiding occupational exposure to blood is the primary way to prevent transmission of bloodborne illnesses among health care personnel. Depending on the medical procedure involved, Standard Precautions may include the appropriate use of personal protective equipment (e.g., gloves, masks, and protective eyewear).

50. What blood tests are used to detect HCV infection? • Screening tests for antibody to HCV (anti-HCV) • enzyme immunoassay (EIA) • enhanced chemiluminescence immunoassay (CIA) • Recombinant immunoblot assay (RIBA) • Qualitative tests to detect presence or absence of virus (HCV RNA polymerase chain reaction [PCR]) • Quantitative tests to detect amount (titer) of virus (HCV RNA PCR)