Hepatitis A-E Viruses

1. Hepatitis A-E Viruses An Overview

2. What is hepatitis? • Hepatitis is an inflammation of the liver, that may be caused by: viral infection, other infections, autoimmune process, or exposure to certainchemicals or drugs (alcohol abuse) • The condition can be a short episode (acute) or a prolonged illness (chronic). • There are many hepatitis viruses; the three most common are called hepatitis A, B and C.

3. The condition can be self limiting (healing on its own) or can progress to scarring of liver. • Acute hepatitis is when it lasts less then 6 months and chronic hepatitis is when it persists longer. • It may run without clinical symptoms. The patient becomes symptomatic when the disease impairs liver functions.

4. symptoms of Acute Hepatitis • flu-like symptoms: • muscle and joint aches, • fever, • feeling sick or vomiting, • diarrhea • Headache • loss of appetite • aversion of smoking among smokers • dark urine • yellowing of the eyes and skin i.e. jaundice (צהבת) and abdominal discomfort.

5. symptoms of chronic hepatitis • Majority of patients will remain asymptomatic • Many experience return of symptoms related to acute hepatitis • Later - jaundice • abdominal fullness from enlarged liver or spleen • fever and fluid retention • cirrhosis - extensive damage and scarring of liver • weight loss • In the case of autoimmune hepatitis: acne, abnormal menstruation, lung scarring, inflammation of the thyroid gland and kidneys

6. Hepatitis A Virus

7. Family Picornaviridae • 1.Genus Enterovirus • Type Species poliovirus 1 • 2.Genus Rhinovirus • Type Species human rhinovirus 1A • 3.Genus Hepatovirus • Type Specieshepatitis A virus 1 • 4.Genus Cardiovirus • Type Species encephalomyocarditis viris • 5.Genus Aphthovirus • Type Species foot-and-mouth disease virus

8. Hepatitis A • is caused by a picornavirus. • non-enveloped • ssRNA virus with • a single serotype (one surface antigens)

9. Hepatitis A • It causes an acute form of hepatitis and does not have a chronic stage. • Hepatitis A does not usually cause permanent liver damage and patients make a complete recovery after a few months. • Very occasionally, however, there may be serious, even fatal, complications (approximately 100 deaths each year in the U.S ) • The time between the infection and the start of the illness can run from 15 to 45 days • After the initial phase, which may last from a few days to several weeks, the symptoms subside, but tiredness may continue for months. • The patient's immune system makes antibodies against hepatitis A -> immunity against future infection. • The patient is advised to rest, stay hydrated and avoid alcohol.

10. HAV – transmission • It is transmitted by: • the oro-fecal route, • can be spread through personal contact (including sex contact and exposureto infected Blood), • consumption of raw sea food or drinking contaminated water or contaminated food.

11. HAV - prevention • A vaccine is available that will prevent infection from hepatitis A for life. • Also strict personal hygiene and the avoidance of raw and unpeeled foods can help prevent an infection.

12. Hepatitis A Prevention - Immune Globulin • Pre-exposure • travelers to intermediate and high HAV-endemic regions • Post-exposure (within 14 days) Routine • household and other intimate contacts Selected situations • institutions (e.g., day care centers) • common source exposure (e.g., food prepared by infected food handler)

14. HAV - Epidemiology • Hepatitis A outbreaks still occur in developed countries • The most widespread hepatitis A outbreak in American history afflicted at least 640 people (killing 4) in north-eastern Ohio and south-western Pennsylvania in late 2003. The outbreak was blamed on tainted green onions at a restaurant in Monaca, Pennsylvania.

15. Hepatitis A Vaccination Strategies Epidemiologic Considerations • Many cases occur in community-wide outbreaks • no risk factor identified for most cases • highest attack rates in 5-14 year olds • children serve as reservoir of infection • Persons at increased risk of infection • travelers • homosexual men • injecting drug users

16. Hepatitis B Virus

17. Hepatitis B • a member of the Hepadnavirus family • Symptoms of the acute illness: liver inflammation, vomiting, jaundice, and rarely, death. • Chronic hepatitis B may cause liver cirrhosis which may then lead to liver cancer, a fatal disease with very poor response to current chemotherapy. • Hepatitis B has an incubation period of about two months and will often last for as long as six months before symptoms diminish.

18. Hepatitis B - transmission • Hepatitis B virus is spread through body fluids, such as blood, semen, saliva and vaginal secretions. • unprotected sexual contact • blood transfusions, • re-use of contaminated needles and syringes, • transmission from mother to child during childbirth • and so on.

19. Concentration of Hepatitis B Virus in Various Body Fluids Low/Not High Moderate Detectable blood semen urine serum vaginal fluid feces wound exudates saliva sweat tears breastmilk

20. Hepatitis B - immune response • During HBV infection the host immune response is responsible for both liver damage and viral clearance. • virus-specific cytotoxic T lymphocytes kill infected cells • However, cytotoxic T lymphocytes also contribute to the liver injury.

21. HBV - structure • enveloped • an icosahedral nucleocapsid, • The outer envelope contains embedded proteins which are involved in viral binding of, and release into, susceptible cells. • Virion shape is generally spherical with a diameter of 40 - 48 nanometers (nm) but other forms exist ( These are not infectious). • The DNA genome is not segmented • partially double-stranded, forms an open circle. • The virus can be divided into four major serotypes based on antigens present on its envelope

22. Hepatitis B • Attachment • Uptake • Repair of (+) DNA strand • DNA translocation • (-) strand is transcribed • mRNAs transport • Pregenome translation to P • Pregenome translation to capsid protein • Packaging • RT to (-) DNA strand 12. Recirculation 14 Envelope acquiring 15 Exocytosis

23. HBV - reverse transcription • Hepatitis B is one of a few known non-retroviral viruses which employ reverse transcription as a part of its replication process. • HIV also uses reverse transcription, but unlike HBV it is a retrovirus.

24. HBV - epidemiology • Hepatitis B is recognized as endemic in China and various other parts of Asia. • The proportion of the world's population currently infected with the virus is 3 to 6% • In low prevalence areas, such as United States, injection drug abuse and unprotected sex are the primary methods of transmission • In moderate prevalence areas, the disease is predominantly spread among children. • In high prevalence areas, such as South East Asia, transmission from mother to a child is most common.

26. Diagnosis • detection of hepatitis B virus infection involves serum or blood tests that detect either viral antigens (proteins produced by the virus) or antibodies produced by the host. • HBsAg - detects viral antigens , used as a general marker of infection. • HBsAb - detects antibodies produced by the host, used to document recovery and/or immunity to HBV infection. • anti-HBc IgM - marker of acute infection. • anti-HBcIgG - past or chronic infection. • HBeAg - indicates active replication of virus and therefore infectiveness. • Anti-Hbe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV. • More recently, PCR (polymerase chain reaction)tests have been developed to detect and measure the amount of viral DNA. These tests are more accurate than HBeAg and are useful to assess a person's infection status and to monitor treatment.

27. Hepatitis B Infection Rapid Test (HbsAg) and Hepatitis B Vaccine Rapid Test (HBsAb)Product Origin:P.R.China

28. HBV-Treatment • antiviral drugs: lamivudine • and immune system modulators: interferon alpha (Uniferon). • In general, each works by reducing the viral load, thus helping a body's immune system clear the infection. • Lamivudine - reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance. • Interferon – (interferons are proteins produced by the cells of the immune system in response to foreign agents such as viruses). for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%. • Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg. • Infants born to mothers known to carry hepatitis B can be treated with antibodies to the hepatitis B virus (hepatitis B immune globulin or HBIg). When given with the vaccine within twelve hours of birth, the risk of acquiring hepatitis B is reduced 95%. This treatment also allows a mother to safely breastfeed her child. • An individual exposed to the virus who has never been vaccinated may be treated with HBIg immediately following the exposure. For instance, a health care worker accidentally stuck by a needle used in a hepatitis B carrier would qualify. Treatment must be soon after exposure, however.

29. HBV-Prevention • Vaccination - highly effective recombinant vaccines are now available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given routinely to neonates as universal vaccination in many countries. • Infants born to mothers known to carry hepatitis B can be treated with antibodies to the hepatitis B virus (hepatitis B immune globulin or HBIg). When given with the vaccine within twelve hours of birth, the risk of acquiring hepatitis B is reduced 95%. This treatment also allows a mother to safely breastfeed her child. • An individual exposed to the virus who has never been vaccinated may be treated with HBIg immediately following the exposure. For instance, a health care worker accidentally stuck by a needle used in a hepatitis B carrier would qualify. Treatment must be soon after exposure, however. • Hepatitis B Immunoglobulin - Other measures - screening of blood donors, blood and body fluid precautions.

30. Hepatitic C

31. Transmission of Hepatitis C - “oldies” • The infection can cause liver inflammation that is often asymptomatic • chronic hepatitis can result later in cirrhosis and liver cancer. • Hepatitis C also spreads via body fluids. The most common routes of infection are sexual contact and using contaminated needles for intravenous drug abuse. • Effective blood-screening procedures have greatly reduced the chances of hepatitis C infection from blood transfusions. • Unlike hepatitis A and B, there is no vaccine to prevent hepatitis C infection.

32. HCV -transmission • is spread by blood-to-blood contact • increased risk for those who have a history of: • intravenous drug use, • inhaled drug usage, • tattoos, • or who have been exposed to blood via unsafe sex or social practices • blood products, or solid organs from a donor whose blood contained HCV. • long-term kidney dialysis ( shared supplies/equipment with infected person ) • Infection from mother at birth via her blood (About 4 out of every 100 infants born to HCV infected women become infected).

33. Hepatitis C - Clinical Features Incubation period: Average 6-7 wks Range 2-26 wks Clinical illness (jaundice): 30-40% (20-30%) Chronic hepatitis: 70% Persistent infection: 85-100% Immunity: No protective antibody response identified

34. HCV - Acute Hepatitis C • Between 60% to 70% of people infected develop no symptoms during the acute phase. • Symptoms of acute hepatitis C infection include decreased appetite, fatigue, abdominal pain, jaundice, itching, and flu-like symptoms. • The hepatitis C virus is usually detectable in the blood within 1 to 3 weeks after infection, and antibodies to the virus are generally detectable within 3 to 12 weeks. • Approximately 20-30% of persons infected with HCV clear the virus from their bodies during the acute phase • The remaining 70-80% of patients infected with HCV develop chronic hepatitis C

35. HCV - Acute Hepatitis C • Between 60% to 70% of people infected develop no symptoms during the acute phase. • Symptoms of acute hepatitis C infection include decreased appetite, fatigue, abdominal pain, jaundice, itching, and flu-like symptoms. • The hepatitis C virus is usually detectable in the blood within 1 to 3 weeks after infection, and antibodies to the virus are generally detectable within 3 to 12 weeks. • Approximately 20-30% of persons infected with HCV clear the virus from their bodies during the acute phase • The remaining 70-80% of patients infected with HCV develop chronic hepatitis C

36. HCV - chronic Hepatitis C • hepatitis C virus persisting for more than six months • it is often asymptomatic • all people have evidence of inflammation on liver, however, the rate of progression of cirrhosis shows significant variability (from less than 20 years to those that will not develop cirrhosis within their lifetimes(. • Factors that influence the rate of HCV disease progression: age, gender (males have more rapid disease progression than females), alcohol consumption, HIV coinfection, and fatty liver. • symptoms : fatigue, weight loss, flu-like symptoms, muscle pain, fevers, itching, sleep disturbances, abdominal pain, appetite changes, nausea, diarrhea, depression, headachesetc

37. היסטוריה של הפטיטיס הוירוס התגלה רק בשנת 1989. כיום מאמינים שמספר אנשים החולים במחלה רק ילך ויגדל מכמה סיבות: • הציבור לא מודע לסכנת המחלה • יש מספר רופאים בעליי ידע מועט על המחלה • ברוב המקרים לוקח עד 20 שנה עד אשר מחלה מתפתחת למחלה כרונית • החולים אשר משתתפים במחקרים לא משקפים את החולים עם מחלות כבד כרוניות • הוירוס יוצר מוטציות רבות, ולכן קשה לעקוב אחריו • המחקרים שעליהם מבוססים כל הטיפולים, הם מחקרים יחסית ישנים • לא ידועות כל הצורות שבהן הוירוס מועבר

38. The Hepatitis C virus (HCV) • small (50 nm in size) • enveloped, • single-stranded, positive sense RNA • family Flaviviridae • הנגיף עובר מוטציות במהירות, והשינויים בחלבון המעטפת מסייעים לו לחמוק ממערכת החיסון • קיימים לפחות 6 גנוטיפים עיקריים ויותר מ-50 תת- סוגים של HCV

39. Hepatitis C Virus capsid envelope protein protease/helicase RNA-dependent RNA polymerase c22 c-100 33c 5’ 3’ NS3 NS5 core E1 E2 NS2 NS4 hypervariable region

40. מחזור החיים של הפטיטיס C הפטיטיס C חייב להיקשר לתאי כבד על מנת שמחזור החיים שלו יתקיים: • וירוס מתחבר לתא של הכבד בעזרת חלבונים הנמצאים על שכבת השומן • חלבון של וירוס חודר את הפלסמה הממברנית ונכנס לתא • השכבה של החלבון מומסת ומשחררת את RNA • בתא המודבק מתחיל ייצר של ויריונים • RNA חדש משוכפל אלפי פעמיים וזה יוצר את החומר הגנטי בשביל • וירוסים חדשים • ריבוזומים יוצרים את החלבונים לשימוש • נוצרת שכבה שלמה וחדשה של חלבונים • וירוסים חדשים נעים לעבר החלק של הפלסמה הממברנית הצמדים אליה • וכך נוצר ניצן. הפלסמה מעגלת את וירוס ואז משחררת אותו

41. אבחנה של הפטיטיס C • הבדיקה הראשונה לאיתור המחלה מאתרת נוגדנים לנגיף בנסיוב הדם. היא מבוססת על שיטות חיסוניות אנזימטיות EIA • הבדיקה הספציפית ביותר לזיהום היא HCV-RNA, • בשיטה זו אפשר לאתר רמות נמוכות של של RNA של • נגיף בנסיוב הדם. יתרונה של בדיקה זו שהיא ישירה, מאתרת • את הנגיף עצמו. נוכחות של RNA מעידה חד-משמעית על • זיהום פעיל

42. אבחנה של HCV הנוגדן של הפטיטיס C אמור לאבחן אם בן אדם חלה במחלה. אך בשלבים מאוחרים וחריפים זה לא יעיל מכיוון שלוקח עד 4 חודשים לאחר ההידבקות עד שנוגדן מופיע • יותר מ- 80 אחוז האנשים המודבקים בוירוס זה, בסופו של דבר יראו • סימפטומים של הפטיטיס C מה שיוביל למחלות כבד קשות. וזה יכול • להתפתח תוך 20 שנה

43. Prevention of Hepatitis C • Screening of blood, organ, tissue donors • High-risk behavior modification • Blood and body fluid precautions

44. מניעה של הפטיטיס C • להגן על הדם ואיברים שונים בגוף מחשיפה מיותרת • שינוי בהתנהגות של אנשים בעליי אחוז הידבקות גבוה במיוחד • הימנעות מהעברה מיותרת של הדם ונוזלים

45. תרופות נגד • הטיפול הסדנדרטי הוא אינטרפון ((INTERFERON • אלפא. זהו חומר טבעי שהגוף מייצר בתגובה לזיהומים וירליים • שונים ונמצא בגוף. בטיפול אנו נותנים אותו בכמויות גדולות ובזריקות • תת-עוריות, אך החיסרון הוא שהחומר נעלם מן הגוף מהר יחסית ולכן • יש צורך להזריקו מידי יומיים לפחות על מנת להילחם בנגיף. • החל משנת 1996 נותנים שילובים של אינטרפרון עם תרופה אנטי ויראלית Ribavirin. • התרופה הינה בעלת פעילות ממושכת, לפיכך ניתן להזריקה פעם בשבוע בלבד.

46. HCV - epidemiology • An estimated 150-200 million people worldwide are infected with hepatitis C. • Hepatitis C is the leading cause of liver transplant in the United States. • Co-infection with HIV is common • 10,000-20,000 deaths a year in the United States . expectations are that this mortality rate will increase, as those who were infected by transfusion before HCV testing become apparent. • Egypt has the highest seroprevalence for HCV. According to a study published in the Lancet, the virus was spread unintentionally through the Nile valley over two decades by rural health officials giving injections to fight another parasitic disease schistosomiasis.

47. הסיבות למחלות כבד

48. Hepatitis D Virus - HDV • a small negative sense, single-stranded circular RNA virus • it can propagate only in the presence of another virus, the hepatitis B virus (HDV requires HBV for synthesis of envelope protein composed of HBsAg) • Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or via infection of an individual previously infected with HBV (superinfection) • This results in more severe complications compared to infection with HBV alone. • In combination with hepatitis B virus, hepatitis D has the highest mortality rate of all the hepatitis infections of 20%.

49. Hepatitis D (Delta) Virus antigen HBsAg RNA

50. Hepatitis D Virus - Transmission • Percutanous exposures • injecting drug use • Permucosal exposures • sex contact