VIRAL HEPATITIS

INTRODUCTION
y Viral Hepatitis is the preventable public health problem in India. y Acute infection with the hepatitis virus may results in conditions ranging from sub-clinical disease to selflimited symptomatic disease to fulminant hepatic failure. y Adults with hepatitis A or B are usually symptomatic and with hepatitis C are either symptomatic or asymptomatic. y It is responsible for more than 90% cases of both acute and chronic hepatitis y Types A and E cause only acute hepatitis and spread by faecal-oral route y Types B,C,D and G cause both acute & chronic hepatitis and are transmitted by blood and blood products and body fluids

Types and causes of viral hepatitis

Acute Hepatitis - Causes y Hepatitis A virus y Hepatitis B virus y Hepatitis C virus y Hepatitis D virus y Hepatitis E virus y Hepatitis G virus y Cytomegalo, EpsteinBarr, Herpes Simplex, Yellow Fever viruses y TT virus (new) Chronic Hepatitis -Causes y Hepatitis B virus y Hepatitis C virus y Hepatitis D virus y Hepatitis G virus

History of viral hepatitis

y 8th Century

: Infectious Nature of HBV suggested

y 17th-19th Centuries: Outbreaks of epidemics of jaundice

y 1883 y 1908 y 1939-1945

in military and civilian populations during wars : Lurman reports outbreaks of serum hepatitis following vaccination of docters : McDonald postulates that the infectious jaundice is caused by a virus : WWII-A series of outbreaks after vaccination for measles and yellow fever

y 1947 : Mac Callum classifies viral hepatitis into two types-

y y y

Viral hepatitis A---> Infectious hepatitis Viral hepatitis B---> Serum hepatitis 1965: Blumberg discovers Australia antigen (HBsAg) in aborigines and shows presence of antigen at high frequency in patients with leukaemia and children with Down's syndrome 1970: Dane discovers the Dane particle (complete HBV particle) 1972: Discovers HBeAg 1973: Feinstone and Purcell identifies HAV

y 1977: Rizzetto describes delta antigen HDV y 1983: Recovery of HEV y 1988: Chiron group (Choo, Kuo, Houghton) closes and identifies HCV. y 1995: Abbot group reports GB Virus-C (GBV-C) and Genelabs group reports in 1996 hepatitis y 1996: Chang's group at NTUH reports in JAMA the successful prevention of HBV infection by nation-wide vaccination on new born babies launched in 1984 in Taiwan. y 1997: Chang's group at NTUH reports in NEJM a decrease in annual incidence rate of hepatocellular carcinoma in children ascribed to nation-wide vaccination against HBV on newborn babies launched in 1984 in Taiwan.

Viral Hepatitis- Historical perspectives

INFECTIOUS
A E

ENTRICALLY

VIRAL HEPATITIS

NANB

F F,

SERUM

B B

PARENTALLY

HEPATITIS A

y The causative agent is hepatitis A virus (HAV) y Family Picornaviridae; genus Hepatovirus y Prevalence of HAV is inversely proportional to the socio-economic class y Major public health problem, 1.4 million cases reported each year worldwide. y In developing countries, pediatric disease and in developed countries, disease of adults.

DISTRIBUTION- World-wide
y Approximately 1.4 million cases reported every year y In USA, reported cases ( American Academy of Paediatrics)
1981 1990 1995 57,929 (45% HAV) 31,441 31,582

y HAV is the most common of the acute hepatitis in United States. y In Shinghai (China), 300,000 cases of hepatitis A and 32 deaths (

attack rate of 4083/100,000 population) were reported in 1988.

Problems in India
y 100,000 cases of viral hepatitis per annum are being reported. y Initially HAV was know as the infectious or epidemic hepatitis virus because of its typical association with epidemics caused by contaminated water and food worldwide. y Mortality : less than 1% y Morbidity : Patient feel ill and confined to bed up to 6 weeks and severity depends upon the nutritional status and immunodeficiency and the general state of health.

Immunity
y One attack confers life long immunity. y Developed countries- 95% Immunity. y Developing countries- less than 50%.

Resistance
y HAV-highly infectious and epidemic. y Resistant to unfavourable environmental conditions(water treatment and disinfection process) y 0.5 mg/l of residual chlorine ensure safety against HAV.

Mode of transmission:
y Close personal contact (e.g., household contact, sex contact, child day care centres) y Contaminated food, water (e.g., infected food handlers, raw shellfish) y Blood exposure (rare) (e.g., injecting drug use, transfusion)

Hepatitis A - Clinical Features

y Incubation period: y

y y

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 15% of people infected with HAV will have prolonged or relapsing symptoms over a 6-9 month period.

Laboratory diagnosis
y Acute infection is diagnosed by the detection of HAV-IgM in serum by EIA (detectable within 5-10 days after the onset of symptoms and persisting for up to 6 months after infection) y 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 communityy No risk factor identified for most cases y Highest attack rates in 5-14 year olds y Children serve as reservoir of infection Persons at increased risk of infection y Traveller's y Homosexual men y Injecting drug users

Vaccination
y Inactivated and live attenuated vaccines against HAV

are available. y India do not have definite policies for hepatitis A vaccination.

Prevention
y Proper Hygiene y Sanitation ( clean water source) y Hepatitis A vaccine ( pre and post exposure) y Immunoglobulin (pre and post exposure)

Pre-Exposure Interventions
y Vaccine is recommended for  children under 19 years of age  Travels to countries with high rates of hepatitis A  Drug users  MSM y Immunoglobulin recommended for  Travelers to countries with high rates of hepatitis S who are leaving in <2 weeks

Post-Exposure Intervention (within 14 days)

y Immunoglobulin  Household and other intimate contacts y Vaccination:  common source exposure (e.g., food prepared by infected food handler  institutions (e.g., day care centers)

Hepatitis B
y The causative agent is hepatitis B virus (HBV) y Earlier referred as Serum Hepatitis. y 200-fold higher risk of primary hepatocellular carcinoma

Properties of HBV: y A member of the hepadnavirus group y Circular partially double-stranded DNA viruses y Replication involves a reverse transcriptase. y endemic in the human population and hyperendemic in many parts of the world. y a number of variants y It has not yet been possible to propagate the virus in cell culture Carrier state : y 10% of infants and up to 30% of adults infected by HBV. y 90% of infants , 30% of 1-5 yrs childrens and 6% of adults infected with HBV develop chronic infection. y Chronic carriers can infect others and they are prone to cirrhosis and hepatic carcinoma

Structure-HBV

y Virion also referred to as Dane y y y y

particle (ds-stranded DNA) 42nm enveloped virus Core antigens located in the center (nucleocapsid) Core antigen (HBcAg) e antigen (HBeAg)- an indicator of transmissibility (minor component of the coreantigenically distinct from HBcAg) 22nm spheres and filaments other forms- no DNA in these forms so they are not infectious (composed of surface antigen)these forms outnumber the actual virions

Genome

y There are 4 open reading

y y y

frames derived from the same strand (the incomplete + strand) S - the 3 polypeptides of the surface antigen (preS1, preS2 and S - produced from alternative translation start sites. C - the core protein P - the polymerase X - a trans-activator of viral transcription (and cellular genes?). HBx is conserved in all mammalian (but not avian) hepadnaviruses. Though not essential in transfected cells, it is required for infection in vivo.

HBV Replication:

y Reverse transcription: one of the mRNAs is replicated with a reverse transcriptase making the DNA that will eventually be the core of the progeny virion y RNA intermediate: HBV replicates through an RNA intermediate and produces and release antigenic decoy particles. y Integration: Some DNA integrates into host genome causing carrier state

Epidemiology
y 350,000,000 carriers worldwide y 120,000,000 carriers in China y - the carrier rate can exceed 10% y -15 to 25% of chronically infected patients will die from chronic liver disease y 982,297 liver disease in China 2005 y 50% of children born to mothers with chronic HBV in the US are Asian American Problem: y Highly endemic areas are those where HBsAg prevalence is >10% y Medium endemicity means prevalence between 2 to 10%. India falls in this zone y Low endemicity means prevalence less than 2 %

Global Patterns of Chronic HBV Infections

High (>10%): 45% of global population y lifetime risk of infection >60% y early childhood infections common Intermediate (2%-10%): 43% of global population (2% y lifetime risk of infection 20%-60% y infections occur in all age groups Low (<2%): 12% of global population y lifetime risk of infection <20% y most infections occur in adult risk groups

High risk groups

y People from endemic regions y Babies of mothers with chronic HBV y Intravenous drug abusers y People with multiple sex partners y Haemophiliac's and other patients requiting blood and blood product treatments y Health care personnel who have contact with blood y Residents and staff members of institutions for the mentally retarded

Pathogenicity and Immunity

y Virus enters hepatocytes via blood y Immune response (cytotoxic T cell) to viral antigens expressed on hepatocyte cell surface responsible for clinical syndrome y 5 % become chronic carriers (HBsAg> 6 months) y Higher rate of hepatocellular carcinoma in chronic carriers, especially those who are e antigen positive y Hepatitis B surface antibody likely confers lifelong immunity (IgG anti-HBs) y Hepatitis B e Ab indicates low transmissibility

Concentration of Hepatitis B Virus in Various Body Fluids

High blood serum wound exudates Moderate semen vaginal fluid saliva Low/Not Detectable urine feces sweat tears breast milk

Clinical features
y Incubation period: y Insidious onset of symptoms. y Tends to cause a more severe disease than Hepatitis A. y Clinical illness (jaundice):

Average 60-90 days Range 45-180 days

y Clinical Illness at presentation y Acute case-fatality rate: y Chronic infection: y Premature mortality from chronic liver disease:

<5 yrs: <10% 5 yrs: 30%-50% 1/3 adults-no symptoms 10 - 15% 15%-16% < 5 yrs: 30%-90% 5 yrs: 2%-10% 15%-25%

Laboratory diagnosis
y A battery of serological tests are used for the diagnosis of acute and y y y y y y y

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.

Prevention
Vaccination - highly effective recombinant vaccines Hepatitis B Immunoglobulin (HBIG) -exposed within 48 hours of the incident/ neonates whose mothers are HBsAg and HBeAg positive. Other measures -screening of blood donors, blood and body fluid precautions.

Vaccinate high risk adults: y Healthcare workers y IV drug users y Household contacts of people w/ Hep B y Patients with multiple sexual partners y Men who have sex with men y HD patients y Patients who require repeated transfusions of blood products y Patients with chronic liver disease

Hepatitis B vaccination
Infants: Infants several options that depend on status of the mother y If mother HBsAg negative: birth, 1-2m,6-18m y If mother HBsAg positive: vaccine and Hep B immune globulin within 12 hours of birth, 1-2m, <6m Adults y * 0,1, 6 months Vaccine recommended in y All those aged 0-18 y Those at high risk

Vaccine efficacy
y Positive immune response is

defined as development of anti-HBs at a titre of >10 IU/L y 95% sero-conversion in healthy adults y Post-vaccination testing in healthcare workers/HD pts/pts who are at risk for recurrent exposure 1-2 months after completion of vaccination. y Non-responders complete a second 3-dose vaccination series

Hepatitis C
y Hepatitis C is caused by

infection with the hepatitis C virus (HCV), an enveloped, single stranded, positive sense RNA virus. y Earlier known as posttransfusion non A-non B hepatitis. y Belongs to family Flaviviridae

Features of Hepatitis C
y Salient Features of HCV infection y 12-25% sporadic cases y Asymptomatic in 50% of cases y Undetected up to 10 years y 20% fully recover in 6 months y 5% chronic cases have increased chance of liver

carcinoma. y Prevention

Epidemiology y 3% of world population is infected with HCV. y 170 million individuals are chronic carriers at risk of developing liver cirrhosis and liver cancer. y Over 50% of cases are asymptomatic. y Most common cause of chronic hepatitis

INCUBATION PERIOD : 6-7 weeks (range: 2-26 weeks); CLINICAL FEATURES : 1. Acute HCV infection is often silent, but 2. if evident then diagnosed when there is circumstantial evidence for new infection,such as a recent exposure to a known HCV-infected person or clinical features of acute hepatitis (jaundice, nausea, anorexia, and malaise) with the exclusion of other causes of hepatitis. 3. Acute hepatitis C rarely causes fulminant hepatic failure.

LONGLONG-TERM EFFECTS : 1.50-85% with HCV develop chronic infection, 2.15- 50% of newly infected clear the virus spontaneously. 3.10-15% with chronic HCV infection develop progressive fibrosis of the liver leading to cirrhosis. 4. Hepatocellular carcinoma (HCC) risk is about 1-4% / year. 5. Deaths from chronic liver disease: 1%-5%

TRANSMISSION :HCV is transmitted primarily by : y Direct percutaneous exposures to infectious blood, such as through injection drug use y Transfusion of contaminated blood products y Inefficiently transmitted through sexual contact persons with multiple sexual partners y Mother to child in approximately 5-6% of pregnant women who have chronic HCV infection at the time of delivery. y Tattooing with contaminated needles y HCV is not spread by kissing, sneezing, hugging, coughing, food or water, sharing eating utensils or drinking glasses, or other casual contact.

Risk factors of HCV transmission

 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

DIAGNOSIS : ACUTE: 1) Marked elevations in ALT (> 7 times) with or without symptoms of acute hepatitis; 2) Negative tests for acute hepatitis A (IgM anti-HAV) and acute hepatitis B (IgM anti-HBc); and 3) A positive anti-HCV screening immunoassay (ICT,ELIZA, CIA) that is confirmed with either: 1. an immunoassay! 2. or a supplemental test, e.g., recombinant immunoblot assay (RIBA ). 3. HCV RNA may be detected by PCR 1-3 weeks after exposure, but viremia may be transient, i.e., a negative qualitative HCV RNA does not preclude acute HCV infection.

TESTING RECOMMENDATIONS FOLLOWING A KNOWN EXPOSURE: EXPOSURE: 1) nucleic acid test for HCV RNA immediately after exposure, at week 4 and at week 12; 2) anti-HCV by ICT or ELIZA immediately after exposure and at week 12 3) serum ALT and AST immediately after exposure, at week 4 and 12. CHRONIC: A quantitative HCV nucleic acid test, however, is required before initiating antiviral therapy, If the quantitative HCV nucleic acid test is negative, the more sensitive qualitative HCV nucleic acid test (PCR) should be obtained.

Treatment and Prevention

Treatment:
y Antiviral therapy is beneficial in treating persons with acute HCV infection. y Treatment interferon + ribavirin. y No vaccine available

Prevention: y Screening of blood, organ, tissue donors y High-risk behaviour modification y Blood and body fluid precautions

Hepatitis D

y Hepatitis D is caused by the Hepatitis D virus ( HDV) y Defective RNA y Occurs as co- or superinfection with HBV y Parenterally transmitted y Leads to severe course of liver disease. y In 1987, normal immunoglobulin preparations were shown to be anti-delta positive.

Mode of Transmission
 Percutanous exposures
 injecting drug use

 Permucosal exposures
 sex contact

HBV HDV Co-infection

Symptoms ALT Elevated

Titre
IgM anti-HDV

anti-HBs

HDV RNA HBsAg Total anti-HDV

Time Exposure

Prevention
y Pre or post-exposure prophylaxis to prevent HBV

infection. y Education to reduce risk behaviours among persons with chronic HBV infection.

Hepatitis E
y HEV was confirmed in

1970s and early 1980s. y Initially referred to as enterically transmitted (or epidemic) non-A, non-B hepatitis(NANB).

Distribution
y HAV and HEV are associated with poor standards of sanitation. y HEV has been recorded predominantly in Afghanistan, China, India, Nepal, Pakistan and in parts of Central Asia, Mexico and in parts of Africa.

INDIA y Common cause of Acute Fulminant Hepatitis in adults. y Large outbreaks associated with sewage contaminated drinking water include 1 in 1954 involving approximately 40,000 cases in Delhi, India. y In 1991, 79,000 cases were reported in Kanpur, India. y Several outbreaks between 1989 and 1999 in AP, MP, Delhi, Ahmedabad, Rajasthan have been investigated by NICD. 80% of cases were 15 years and above. y Males > Females

Transmission: y Faecal-oral route.(water-borne, food-born outbreaks) y Person to person transmission is uncommon. Immunity: y Immunity has no role Mortality: y Less than 1 % y HEV causes fulminant hepatitis and high fatality in pregnant women. y Case fatality 20-40% Animal Reservoir: y HEV zoonotic member y Detected in animal excreta(cows, pigs, goats and rodents)

Incubation period: y 2 weeks to 2 months (mean-40 days) Clinical features: y Fever (disappears by the time of jaundice appears) y Loss of appetite y Feeling of general ill health y Abdominal discomfort y jaundice Laboratory findings: ALT>2.5 times of upper limit Serum Bilirubin> 2 mg%

Prevention and Control

y Personal Hygiene and environmental sanitation y Ensure safe water supply y High level of residual chlorine, at least 0.5 ppm y Virus is killed by boiling of water Anticipatory Action y Ensure water quality monitoring on regular basis in addition to sanitary service and inspections by health agencies and suppliers. y Disease surveillance through health facilities and institutions. y People participation and education of community on all aspects of prevention of Hepatitis by their own action.

Hepatitis F
y Name was proposed following reports of Hepatitis

cases associated with water-borne transmission of virus distinguishable from HAV and HEV. y Existence is not proven, but cases have been reported in India, Italy, UK and USA.

Hepatitis G
AGENT:HGV is RNA virus and is similar to HCV but AGENT: only has 25 amino acids. y The virus is named after GB a 34 year-old surgeon who contracted hepatitis and died from it.His serum was able to infect monkeys and the "GB agent" was passaged in monkeys over the years. In 1995-96 the virus was identified as a distinct virus different from other human hepatitis viruses (A, B, C, D, E) and was named after the surgeon as HGV y Three genotypes of this virus were identified by investigators at Abbott Labs, and termed GB-A, GB-B and GB-C. GB-A and GB-B are likely tamarin viruses; GB-C can infect humans.

CLINIAL FEATURES: FEATURES: y Hepatitis G virus infection is usually "clinically silent" or mild hepatitis and nearly always chronic y Progression to cirrhosis with chronic hepatitis G infection is probably very low. y Some studies report chronicity as high as HCV (up to 70 % ) y Non-hepatic manifestations of this virus may well exist DIAGNOSIS: DIAGNOSIS: Only PCR is available in Agha Khan and SKH and costs more than 2000 rupees per test TREATMENT: Mainly supportive. In HBC+HGV and TREATMENT: HBV+HGV co-infection IFN + RBZL are effective.

TT Virus (Torque Teno Virus )

y Belongs to Circoviridae family y Human virus with single stranded circular DNA genome y TTVs are prevalent in non-human primates and human TTV can cross-infect y First reported in Japan (1997)

SEN virus
y SEN virus (SEN-V) is a blood-borne, single-stranded,

non-enveloped DNA virus y Concurrent infections with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus type 1 . y Cause post-transfusion hepatitis