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HEPATITIS VIRUSES

SHAH RUKH (FA08- BBS- 009)HIJAB HAFEEZ (FA08- BBS- 011)

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CONTENTS

• INTRODUCTION TO HEPATITIS• HEPATITIS A• HEPATITIS B• HEPATITIS C• HEPATITIS D• HEPATITIS E• HEPATITIS G

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HEPATITIS• Hepatitis means "inflammation of the liver." • Disorder in which viruses or other mechanisms

produce inflammation in liver cells, resulting in their injury or destruction.

• All hep viruses can cause an acute form of liver disease. Some specific hep viruses (B, C, and D), and some non-viral forms of hepatitis, can cause chronic liver disease.

• In some cases, acute hepatitis develops into a chronic condition, but chronic hepatitis can also occur on its own

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Types of Viral hepatitis

• Viral hepatitis is of 6 types: Hepatitis A (HAV) Hepatitis B (HBV) Hepatitis C (HCV) Hepatitis D (HDV) Hepatitis E (HEV) Hepatitis G (HGV)

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Hepatitis A

• CLASSIFICATION: Group: Group IV ((+) ssRNA) Family: Picornaviridae Genus: Hepatovirus Specie: Hepatitis A virus• Hepatitis A infection does not cause chronic

liver disease and is rarely fatal, but it can cause debilitating symptoms.

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EPIDEMICS WORLDWIDE

• Epidemics related to contaminated food or water can erupt explosively, such as an epidemic in Shanghai in 1988 that affected about 300,000 people.

• There were 30,000 cases of Hepatitis A reported to the CDC in the U.S. in 1997. The agency estimates that there were as many as 270,000 cases each year from 1980 through 2000.

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Estimated and reported cases of hepatitis A in the United States. Rates have fallen significantly since 1991 when routine

vaccination of children was started. (Image courtesy of the CDC).

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Mode of Transmission

• Hepatitis A is transmitted by enteric, that is digestive or by fecal routes

• Poor hygiene and poor sanitary conditions in some countries lead to high rates of infection.

• Some areas of the world are particularly prone to hepatitis A virus e.g. India, South America, Bangladesh, and Central America.

• 1/3rd of people in the U.S of America have been exposed to the hepatitis A virus.

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Symptoms• Symptoms usually develop between 2 and 6

weeks after infection• Most common symptoms are: Nausea, Vomiting ,Diarrhea(especially in

children) ,Low-grade fever, Loss of appetite Rash, Tiredness, fatigue, Jaundice, Urine(dark brownish in color),Pain in area of liver

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Genome structure

• The Hepatitis virus (HAV) is a Picornavirus; it is non-enveloped and contains a single-stranded RNA packaged in a protein shell.

• There is only one serotype of the virus, but multiple genotypes exist.

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Replication Mechanism• HAV enters the bloodstream through the

epithelium• Reaches to its target, the liver, where it

multiplies within hepatocytes and Kupffer cells• Within the liver hepatocytes the RNA genome

is released from the protein coat and is translated by the cell's own ribosomes.

• The incubation period is 15–50 days and mortality is less than 0.5%.

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Contd…

• Unlike other members of the Picornaviruses this virus requires an intact eukaryote initiating factor 4G (eIF4G) for the initiation of translation. The requirement for this factor results in an inability to shut down host protein synthesis unlike other picornaviruses

• Precisely how this strategy works is not quite clear yet.

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Host Immune response

• In hepatitis A, the presence of anti-HAV IGM is detectable about 3 weeks after exposure, its titre increases over 4 to 6 weeks, then declines to nondetectable levels generally within 6 months of infection.

• Anti-HAV IGA and IgG are detectable within a few days of the onset of symptoms. IgG antibodies persist for years after infection and provide lifelong immunity.

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Vaccination• Vaccine protects against HAV in more than 95% of

cases for longer than 20 years• It contains inactivated hepatitis A virus providing

active immunity against a future infection.• Vaccine was first phased in 1996 for children in high-

risk areas, and in 1999 it was spread to areas with elevating levels of infection

• An initial dose provides protection starting two to four weeks after vaccination; the second booster dose, given six to twelve months later, provides protection for over twenty years.

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Hepatitis B• Classification: Group: Group VII (ds-DNA-RT) Family: Hepadnaviridae Genus: Orthohepadnavirus Specie: Hepatitis B virus• Potentially life-threatening liver infection• It is a major global health problem and the

most serious type of viral hepatitis.

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Epidemics worldwide

• As of 2010, China has 120 million infected people, followed by India and Indonesia with 40 million and 12 million respectively

• It is estimated that 350 million individuals worldwide are infected with the virus, which causes 620,000 deaths worldwide each year.

• According to the Centers for Disease Control (CDC), approximately 46,000 new cases of hepatitis B occurred in the United States in 2006.

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Mode of Transmission

• Having Hepatitis B does not necessarily mean that he or she is infectious to other people,

• Hepatitis B is transmitted through contaminated blood, sweat, tears, saliva, semen, saliva, vaginal secretions, menstrual blood and breast milk.

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Symptoms• Hepatitis B virus can cause an acute illness

with symptoms that last several weeks, including yellowing of the skin and eyes (jaundice), dark urine, extreme fatigue, nausea, vomiting and abdominal pain.

• HBV can also cause a chronic liver infection that can later develop into cirrhosis of the liver or liver cancer.

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Genomic Structure• Smallest enveloped animal viruses, with a virion

diameter of 42 nm• The virus particle, (virion) consists of an outer lipid

envelope and an icosahedral nucleocapsid core composed of protein. The nucleocapsid encloses the viral DNA and a DNA polymerase that has reverse transcriptase activity.

• The outer envelope contains embedded proteins which are involved in viral binding of, and entry into, susceptible cells.

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Replication Mechanism

• life cycle of hepatitis B virus is complex• one of a few known non-retroviral viruses which use

reverse transcription as a part of its replication process

• Gains entry by endocytosis• The partially double stranded viral DNA is then

made fully double stranded and transformed into covalently closed circular DNA (cccDNA) that serves as a template for transcription of four viral mRNAs

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Contd…• The largest mRNA, (which is longer than the

viral genome), is used to make the new copies of the genome and to make the capsid core protein and the viral DNA polymerase.

• These four viral transcripts undergo additional processing and go on to form progeny virions which are released from the cell or returned to the nucleus and re-cycled to produce even more copies.

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Host immune response

• Primary infection leads to an IgM and IgG response to HBcAg shortly after the appearance of HBsAg in serum, at onset of hepatitis.

• Anti-HBs appear in serum only several weeks later

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Vaccination

• Vaccine is administered in either two-, three-, or four-dose schedules into infants and adults, which provides protection for 85–90% of individuals.

• Protection has been observed to last 12 years in individuals who show adequate initial response to the primary course of vaccinations, and that immunity is predicted to last at least 25 years.

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Hepatitis C• Classification: Group: Group IV ((+) ss RNA) Family: Flaviviridae Genus: Hepacivirus Specie: Hepatitis C virus• HCV infection is the leading cause of liver

transplantation in the U.S and is a risk factor for liver cancer.

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Epidemics Worldwide• Worldwide, it is estimated that 130-170

million people are living with chronic hepatitis C infection, that it infects 3-4 million people per year, and that more than 350,000 people die from hepatitis C related diseases each year

• Countries with particularly high rates of infection include Egypt (22%), Pakistan (4.8%) and China (3.2%)

• There are about 35,000 to 185,000 new cases a year in the U.S.

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Co-infection with HIV

• Approximately 35% of patients in the USA infected with HIV are coinfected with the hep C virus, mainly because both viruses are blood-borne and are present in similar populations

• It has been demonstrated in clinical studies that HIV infection causes a more rapid progression of chronic hepatitis C to cirrhosis and liver failure.

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Mode of Transmission• Most common route of transmission is

needles shared among users of illicit drugs. • HCV is transmitted most efficiently through

exposure to infected blood. • HCV infection also can be passed from mother

to unborn child• A small number of cases are transmitted

through sexual intercourse.

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Symptoms

• About 75% of people have no symptoms when they first acquire HCV infection. The remaining 25% may complain of fatigue, loss of appetite, muscle aches or fever. Yellowing of the skin or eyes (jaundice) is rare at this early stage of infection.

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Genomic structure

• HCV has a positive sense single-stranded RNA genome which consists of a single ORF that is 9600 nucleotide bases long. This single ORF is translated to produce a single protein product, which is then further processed to produce smaller active proteins.

• Structural proteins made by the hepatitis C virus include Core protein, E1 and E2; nonstructural proteins include NS2, NS3, NS4, NS4A, NS4B, NS5, NS5A, and NS5B.

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Hepatitis C Genome

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Replication Mechansim

• RNA replication takes places via the viral RNA-dependent RNA polymerase NS5B, which produces a negative-strand RNA intermediate. The negative strand RNA then serves as a template for the production of new positive-strand viral genomes. Nascent genomes can then be translated, further replicated, or packaged within new virus particles. New virus particles are thought to bud into the secretory pathway and are released at the cell surface.

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Genotypic Distribution

• Based on genetic differences the hep C virus species is classified into six genotypes (1-6) with several subtypes within each genotype

• Distribution of HCV genotypes varies globally. For example, in North America, genotype 1a predominates followed by 1b, 2a, 2b, and 3a. In Europe, genotype 1b is predominant followed by 2a, 2b, 2c, and 3a. Genotypes 4 and 5 are found almost exclusively in Africa.

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Vaccination

• Unlike hepatitis A and B, there is currently no vaccine to prevent hepatitis C infection. The genetic diversity of HCV is one reason that it has been difficult to develop an effective vaccine since the vaccine must protect against all genotypes as genotyping is important to guide treatment because some viral genotypes respond better to therapy than others.

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INF Treatment

• Treatment of hepatitis C infection based on interferon alfa as an immune modulator. Response rates have been modest when it was used as monotherapy (10% in genotype 1 and 30% at best in genotypes 2 and 3)

• The addition of ribavirin, a nucleoside analogue and an inhibitor of viral replication, has improved the SVR rate to approximately 50% (46% in genotype 1 and 76% in genotypes 2 and 3)

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Recently introduced treatment

• Most recently introduced treatment is pegylated interferon, a form of interferon covalently bound to a large, inert, polyethylene glycol molecule. The combination serves to prolong the serum half-life increasing the duration of action.

• If patients are able to complete a full course of treatment at optimal doses, SVR rates may be as high as 88% in genotypes 2 and 3 patients and up to 50% in those with genotype 1

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SVR rates during INF treatments in genotypic 1, 2 and 3

Interferon Duration (months) SVR genome 1 (%)

SVR genome 2 and 3 (%)

Interferon plus ribavarin

6 10% 20%

Pegylated interferon

6-12 21% 45%

Pegylated interferon plus ribavirin

6-12 46% 76%

Pegylated interferon+ribavirin in patients with chronic HCV and low viral load (<2 million copies/mL)

6-12 56% 81%

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HEPATITIS D

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Hepatitis D

• Most virulent form of hepatitis but most flawed

• Requires HBsAg

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GENOME

• 1700 bases small circular RNA• RNA encodes a protein Delta Antigen• Negative sense ssRNA

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TYPES OF INFECTION

• Co Infection• Super Infection

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CLASSIFICATION

• Family: Not classified• Genus: Deltaviridae• Species: Hepatitis D virus

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SYMPTOMS

• Muscle Fatigue• Joint Pain• Jaundice• Nausea• Vomiting• Dark colored urine• Loss of appetite

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MODE OF TRANSMISSION

• Blood borne• Body fluids and blood exchange• Injecting drug users• Homosexuals

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STRAINS OF HDV

• 3 genotypes• Genotype I: Worldwide• Genotype II: East Asia• Genotype III: South America

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REPLICATION MECHANISM

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PREVENTION AND TREATMENT

• Avoiding HBV infection• Avoiding body fluid or blood contact with the

affected person

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DIAGNOSIS

• IgM and IgG• Testing the blood serum levels

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HEPATITIS E

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Hepatitis E

• Leading cause of acute liver damage• Africa, Central Asia and Mexico• Accounts for half of the acute forms of viral

hepatitis• 20 percent of world’s population

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MODE OF TRANSMISSION

• Water borne• Often via food contaminated with feces of the

infected person

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DEATH RATES

• 1 to 2 percent in adults• Acute form not chronic

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SYMPTOMS

• Malaise (discomfort)• Anorexia• Abdominal pain• Diarrhea• Fever• Dark colored urine• Muscle fatigue/pain• Pale colored stool

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GENOTYPES

• Identified by the country of origin• Burmese• Mexican • United States• Genotype 1, 2, and 3 respectively

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CLASSIFICATION

• Related to calcivirus• More close to Rubella virus• 34nm, +ve sense RNA• Round and icosahedral and non enveloped

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REPLICATION MECHANISM

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TESTING AND DIAGNOSIS

• Testing the HEV specific antibodies in the blood

• In acute or asymptomatic liver enzymes: ‘alanine aminotransferase’ (ALT) and ‘gamma glutamyl transpeptidase’ (GGT) are tested

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TREATMENT

• No vaccine is available• Only treatment is prevention• Ribavirin and Interferon alpha may inhibit HEV

replication

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HEPATITIS G

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Hepatitis G

• Flaviviradae• Single stranded RNA virus• 27 percent homology with HCV• Co infection with GBV-C but no evidences of

HGV to cause infection

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SYMPTOMS AND TRANSMISSION

• Asymptomatic• Does enter the blood stream but no evidences

of acute or chronic liver disease• Transmitted by blood transfusion• Sexual contact• Organ Transplants• Injecting Drug Users• Dialysis and Homosexual men

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TESTING AND TREATMENT

• No serological test available• No PCR tests• No preventive measures administered

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TRENDS

• Reported in adults and children worldwide• Found in about 1.5% of blood donors in the

United States. • Infection has been reported in 10% to 20% of

adults with chronic HBV or HCV infection, indicating that co-infection is a common occurrence.