Viral Hepatitis Richard J. Ziegler

Introduction (1) Hepatitis with an infectious etiology is primarily a viral disease. At least seven viruses cause hepatitis; three are also associated with primary hepatocellular carcinoma. Acute infections caused by these viruses cannot be distinguished clinically from each other, but serum enzyme changes allow differentiation from other liver disease.

Introduction (2) Several viruses produce chronic infections associated with “carrier” individuals. Routes of infection are unique for each virus. Vaccines and human gamma globulin preparations are available for protection from some of these viruses.

Clinical Disease Majority of infections are asymptomatic. Disease includes anorexia, nausea, vomiting, right upper quadrant pain, and increased serum levels of liver enzymes AST and ALT. Jaundice occurs late in the disease and is frequently not present.

Hepatitis Viruses Enterically transmitted hepatitis is caused by Hepatitis A (HAV) and Hepatitis E (HEV) viruses. Parenterally transmitted hepatitis is caused by Hepatitis B (HBV), Hepatitis C (HCV), and Hepatitis D (HDV) viruses. Mosquito bite transmitted hepatitis is caused by the Yellow Fever virus. Other viruses like HSV, CMV, EBV, and rubella can cause acute hepatitis as part of their systemic disease.

Viral Hepatitis - Historical Perspectives Enterically transmitted “Infectious” A E Viral hepatitis NANB Parenterally transmitted “Serum” B D C F, G, TTV ? other 2

Type of Hepatitis A B C D E Source of feces blood/ blood/ blood/ feces virus blood-derived blood-derived blood-derived body fluids body fluids body fluids Route of fecal-oral percutaneous percutaneous percutaneous fecal-oral transmission permucosal permucosal permucosal Chronic no yes yes yes no infection Prevention pre/post- pre/post- blood donor pre/post- ensure safe exposure exposure screening; exposure drinking immunization immunization risk behavior immunization; water modification risk behavior modification 3

Hepatitis A Virus 6

Introduction to HAV Hepatitis HAV exists in only one serotype. Clinical disease is milder or asymptomatic in young children. Virus shedding precedes symptoms by about two weeks. A general review of HAV and its clinical disease may be found at: http://www.cdc.gov/ncidod/diseases/hepatitis/a/index.htm

Hepatitis A - Clinical Features Incubation period: Average 30 days Range 15-50 days Jaundice by <6 yrs, <10% age group: 6-14 yrs, 40%-50% >14 yrs, 70%-80% Complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Chronic sequelae: None 7

Hepatitis A Infection Typical Serological Course Total anti-HAV Titre Symptoms Titre ALT Fecal HAV IgM anti-HAV 1 2 3 4 5 6 12 24 Months after exposure 9

Hepatitis A Virus Transmission Close personal contact (e.g., household contact, sex contact, child day care centers) Contaminated food, water (e.g., infected food handlers in restaurants, raw shellfish) Blood exposure (rare) (e.g., injecting drug use, transfusion) 11

Laboratory Diagnosis Acute infection is diagnosed by the detection of HAV-IgM in serum by EIA or ELISA for HAV antigen in feces. Past Infection i.e. immunity is determined by the detection of HAV-IgG by EIA.

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 18

HAV Vaccines Havrix and VAQTA are formalin inactivated virion preparations that can be used for individuals 12 mos. and older. Twinrix vaccine is used to protect those 18 and older from both HAV and HBV and is a combination of Havrix and Energix-B (a purified recombinant surface antigen preparation of HBV).

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) 27

HAV Active and Passive Immunizations Details Details are found at the following websites: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5507a1.htm and http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5037a4.htm

Introduction to HEV Hepatitis HEV is not endemic in USA. Disease is usually associated with travel to an endemic area. A general review of HEV and its clinical disease may be found at: http://www.cdc.gov/ncidod/diseases/hepatitis/e/index.htm

Hepatitis E Virus 26 26 26

Hepatitis E - Clinical Features Incubation period: Average 40 days Range 15-60 days Case-fatality rate: Overall, 1%-3% Pregnant women, 15%-25% Illness severity: Increased with age Chronic sequelae: None identified 27 27 27

Hepatitis E Virus Infection Typical Serologic Course Symptoms ALT IgG anti-HEV Titer IgM anti-HEV Virus in stool 1 2 3 4 5 6 7 8 9 10 11 12 13 Weeks after Exposure 28 28 28

Epidemiologic Features Hepatitis E - Epidemiologic Features Most outbreaks associated with fecally contaminated drinking water. Several large epidemics have occurred in the Indian subcontinent and the USSR, China, Africa and Mexico. In the United States and other nonendemic areas, where outbreaks of hepatitis E have not been documented to occur, a low prevalence of anti-HEV (<2%) has been found in healthy populations. The source of infection for these persons is unknown. Minimal person-to-person transmission. 29 29 29

Prevention and Control Measures for Travelers to HEV-Endemic Regions Avoid drinking water (and beverages with ice) of unknown purity, uncooked shellfish, and uncooked fruit/vegetables not peeled or prepared by traveler. IG prepared from donors in Western countries does not prevent infection. Unknown efficacy of IG prepared from donors in endemic areas. Vaccine? 31 31 31

Hepatitis B Virus 28

Introduction to HBV Hepatitis Virion is called the “Dane particle”. Viral antigens HBs, HBc, and HBe and HBV replication are important (see http://pathmicro.med.sc.edu/virol/hepatitis-virus.htm ). Reverse transcription is involved in replication

Introduction (2)

Introduction (3) Virus infection may lead to acute disease or be asymptomatic. Development of a chronic carrier state is inversely related to the age of infection (perhaps 90% in infected neonates). 350 million carriers worldwide.

Introduction (4) Hepatocellular necrosis is immune-mediated. HBV is associated with PHC (primary hepatocelluar carcinoma). HBx protein has been implicated in PHC. Passive and active immunization as well as antiviral treatment is available.

Hepatitis B - Clinical Features Incubation period: Average 60-90 days Range 45-180 days Clinical illness (jaundice): <5 yrs, <10% 5 yrs, 30%-50% Acute case-fatality rate: 0.5%-1% Chronic infection: <5 yrs, 30%-90% 5 yrs, 2%-10% Premature mortality from chronic liver disease: 15%-25% 29

Spectrum of Chronic Hepatitis B Diseases 1. Chronic Persistent Hepatitis - asymptomatic 2. Chronic Active Hepatitis - symptomatic exacerbations of hepatitis 3. Cirrhosis of Liver 4. Hepatocellular Carcinoma

Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course Symptoms HBeAg anti-HBe Total anti-HBc Titre anti-HBs HBsAg IgM anti-HBc 4 8 12 16 20 24 28 32 36 52 100 Weeks after Exposure 30

Progression to Chronic HBV Infection Typical Serologic Course Acute (6 months) Chronic (Years) HBeAg anti-HBe HBsAg Total anti-HBc Titre IgM anti-HBc 4 8 12 16 20 24 28 32 36 52 Years Weeks after Exposure 31

Outcome of Hepatitis B Virus Infection by Age at Infection 100 100 80 Chronic Infection (%) 80 60 60 Chronic Infection Symptomatic Infection (%) 40 Chronic Infection (%) 40 20 20 Symptomatic Infection Birth 1-6 months 7-12 months 1-4 years Older Children and Adults Age at Infection 34

Global Patterns of Chronic HBV Infection High (>8%): 45% of global population lifetime risk of infection >60% early childhood infections common Intermediate (2%-7%): 43% of global population lifetime risk of infection 20%-60% infections occur in all age groups Low (<2%): 12% of global population lifetime risk of infection <20% most infections occur in adult risk groups 35

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 1 1 1

Hepatitis B Virus Modes of Transmission Sexual - sex workers and homosexuals are particular at risk. Parenteral - IVDA, Health Workers are at increased risk. Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not. Perinatal transmission is the main means of transmission in high prevalence populations. 2 2 2

Diagnosis A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection. HBsAg - used as a general marker of infection. HBsAb - 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. HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

Treatment (1) Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%. Epivir (Lamivudine) - a oral, nucleoside analogue 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. Entecavir (Baraclude) – a recently FDA approved, oral nucleoside transcriptase inhibitor Hepsera (Adefovir dipivoxil) – an oral, nucleoside reverse transcriptase inhibitor with same problems as lamivudine.

Treatment (2) The latest treatment recommendations are at: http://www3.interscience.wiley.com/cgi-bin/fulltext/107630495/HTMLSTART Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg negative.

Prevention Vaccination - highly effective recombinant vaccines (see below) 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. Hepatitis B Immunoglobulin - HBIG may be used to protect persons who are exposed to hepatitis B. It is particular efficacious within 48 hours of the incident. It may also be given to neonates who are at increased risk of contracting hepatitis B i.e. whose mothers are HBsAg and HBeAg positive. Other measures - screening of blood donors, blood and body fluid precautions.

Vaccines (1) Two HBV recombinant subunit vaccines containing HBsAg are available (Recombivax HB and Energix-B). Twinrix, a combination of Havrix and Energix-B is available for those 18 years old and older. Comvax, a combined HBV-H.influenzae type b conjugate vaccine may be used between 6 weeks and 70 years. Pediarix, a combined HBV-diptheria, tetanus, and acellular pertusis-inactivated poliovirus vaccine can not be used before 6 weeks or at an age >7 years.

Vaccines (2) Vaccination for HBV is discussed at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5416a1.htm Vaccination for HAV and HBV is discussed at: http://digestive.niddk.nih.gov/ddiseases/pubs/vaccinationshepab/

Table 2                                                                                            

Introduction to HDV Hepatitis HDV is a defective virus that contains delta antigen and requires HBV for replication. The clinical disease is more severe than HBV hepatitis.

Hepatitis D (Delta) Virus  antigen HBsAg RNA 19 19 19

Hepatitis D - Clinical Features Coinfection severe acute disease. low risk of chronic infection. Superinfection usually develop chronic HDV infection. high risk of severe chronic liver disease. may present as an acute hepatitis. 20 20 20

Hepatitis D Virus Modes of Transmission Percutanous exposures injecting drug use Permucosal exposures sex contact 21 21 21

HBV - HDV Coinfection Typical Serologic Course Titre Symptoms ALT Elevated Titre anti-HBs IgM anti-HDV HDV RNA HBsAg Total anti-HDV Time after Exposure 22 22 22

HBV - HDV Superinfection Typical Serologic Course Jaundice Symptoms Total anti-HDV ALT Titre HDV RNA HBsAg IgM anti-HDV Time after Exposure 23 23 23

Hepatitis D - Prevention HBV-HDV Coinfection Pre or postexposure prophylaxis to prevent HBV infection. HBV-HDV Superinfection Education to reduce risk behaviors among persons with chronic HBV infection. 25 25 25

Introduction to HCV Hepatitis (1) HCV is a flavivirus, an enveloped, s.s. + sense RNA virus. It is the most common cause of transfusion-associated hepatitis and blood-borne infections in USA. Acute form of the disease is milder than hepatitis caused by HAV and HBV and is rarely recognized clinically. 70% of those infected develop chronic disease, a high percentage of which is asymptomatic.

Introduction (2) 6 HVC genotypes and over 50 subtypes exist; positive chronic infection treatment response depends on genotype (types 2 and 3 respond best) HCV accounts for an estimated 1/3 PHC (primary hepatocellular carcinoma) cases. Several HCV nonstructural proteins interact with cell cycle proteins e.g. p53 or their promotors.

Hepatitis C Virus capsid envelope protein protease/helicase RNA-dependent RNA polymerase c22 33c c-100 5’ 3’ core E1 E2 NS2 NS3 NS4 NS5 hypervariable region 7 7 7

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 8 8 8

Chronic Hepatitis C Infection All the manifestations of chronic hepatitis B infection may be seen, albeit with a lower frequency i.e. chronic persistent hepatitis, chronic active hepatitis, cirrhosis, end stage liver disease, and hepatocellular carcinoma. 10-20% of those infected progress past the chronic persistent hepatitis stage to the more serious disease stages.

Hepatitis C Virus Infection Typical Serologic Course anti-HCV Symptoms Titre ALT Normal 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure 10 10 10

Risk Factors Associated with Transmission of HCV Transfusion or transplant from infected donor Injecting drug use Hemodialysis (yrs on treatment) Accidental injuries with needles/sharps Sexual/household exposure to anti-HCV-positive contact Multiple sex partners Birth to HCV-infected mother 11 11 11

14 14 14

Laboratory Diagnosis HCV antibody - generally used with HCV-RNA test to diagnose chronic hepatitis C infection. Not useful in the acute phase as it takes at least 4 weeks after infection before antibody appears. HCV-RNA - various techniques are available e.g. PCR and branched DNA. May be used to diagnose HCV infection in the acute phase. However, its main use is in diagnosing chronic infection and monitoring the response to antiviral therapy.

Treatment (1) Since symptoms during acute infection are rare, it is rarely diagnosed or treated; if diagnosed, a short course combination treatment similar to those for chronic HCV hepatitis is recommended. Presently, the optimal treatment for chronic infection uses a 24 or 48 wk. course of the combination of subcutaneous pegylated (polyethylene glycol-conjugated) alpha interferon and oral ribivirin.

Treatment (2) An excellent discussion of the current thoughts concerning the management of chronic hepatitis C infection is found at: http://www.digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/

Prevention of Hepatitis C Screening of blood, organ, tissue donors High-risk behavior modification Blood and body fluid precautions 15 15 15

Yellow Fever Virus Hepatitis Yellow fever virus (YFV) is a flavivirus the same family as HCV. YFV is acquired through the bite of a mosquito therefore it is an arbovirus. Urban yellow fever involves person to person transmission by domestic mosquitoes. Jungle yellow fever involves monkey to human transfer by arboreal mosquitoes.

Yellow Fever Clinical Disease (1) Short 3-6 day incubation period. Disease may be mild or severe. Initial symptoms include: fever, chills, headache, dizziness, myalgia, and backache followed by nausea, vomiting and bradycardia. Symptoms may resolve or proceed to high fever, jaundice, and renal dysfunction.

Clinical disease (2) Patients either die or recover completely. Illness occurs in Africa and Central and South America.

Prevention and Treatment An excellent live, attenuated virus vaccine using the 17D strain of the virus is available. No antiviral drug therapy is available.