hepatitis a-e viruses
DESCRIPTION
Hepatitis A-E Viruses. Enock Anassi MD, PharmD. Viral Hepatitis - Historical Perspectives. Enterically transmitted. “ Infectious”. A. E. Viral hepatitis. NANB. Parenterally transmitted. B. D. C. “ Serum”. F, G, TTV ? other. Type of Hepatitis. A. B. C. D. E. Source of. - PowerPoint PPT PresentationTRANSCRIPT
Hepatitis A-E Viruses
Enock Anassi MD, PharmD
AA“ Infectious”
“ Serum”
Viral hepatitis
Entericallytransmitted
ParenterallytransmittedF, G, TTV
? other
EE
NANBNANB
BB DD CC
Viral Hepatitis - Historical Perspectives
Source ofvirus
feces blood/blood-derived
body fluids
blood/blood-derived
body fluids
blood/blood-derived
body fluids
feces
Route oftransmission
fecal-oral percutaneouspermucosal
percutaneouspermucosal
percutaneouspermucosal
fecal-oral
Chronicinfection
no yes yes yes no
Prevention pre/post-exposure
immunization
pre/post-exposure
immunization
blood donorscreening;
risk behaviormodification
pre/post-exposure
immunization;risk behaviormodification
ensure safedrinking
water
Type of HepatitisA B C D E
Hepatitis A Virus
HEPATITIS A: signs and symptoms
Nausea and vomiting, anorexia, jaundice
Self limited No chronic disease Stool excretion 2 weeks before and
1 week after appearance
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 hepatitisCholestatic
hepatitisRelapsing
hepatitis Chronic sequelae: None
Hepatitis A - Clinical Features
FecalHAV
Symptoms
0 1 2 3 4 5 6 12
24
Hepatitis A Infection
Total anti-HAV
Titre ALT
IgM anti-HAV
Months after exposure
Typical Serological Course
Close personal contact
(e.g., household contact, sex contact, child day care centers)
Contaminated food, water(e.g., infected food handlers, raw shellfish)
Blood exposure (rare)(e.g., injecting drug use, transfusion)
Hepatitis A Virus Transmission
EndemicityDisease
RatePeak Age
of Infection Transmission Patterns
High Low to High
Early childhood
Person to person;outbreaks uncommon
Moderate High Late childhood/
young adults
Person to person;food and waterborne outbreaks
Low Low Young adults Person to person;food and waterborne outbreaks
Very low Very low Adults Travelers; outbreaks uncommon
Global Patterns of Hepatitis A Virus Transmission
Laboratory Diagnosis
Acute infection is diagnosed by the detection of HAV-IgM in serum by EIA.
Past Infection i.e. immunity is determined by the detection of HAV-IgG by EIA.
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
Hepatitis A Vaccination
StrategiesEpidemiologic Considerations
Pre-exposure travelers to intermediate and high
HAV-endemic regions Post-exposure (within 14 days)
Routine household and other intimate contactsSelected situations institutions (e.g., day care centers) common source exposure (e.g., food prepared by
infected food handler)
Hepatitis A Prevention - Immune Globulin
VIRAL HEPATITIS
HEPATITIS B
Hepatitis B Virus
Incubation period: Average 60-90 daysRange 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%
immunocompetent 5 yrs, 1%-5%
Premature mortality fromchronic liver disease: 15%-25%
Hepatitis B - Clinical Features
Spectrum of Chronic Hepatitis B Diseases
1Chronic Persistent Hepatitis - asymptomatic
2. Chronic Active Hepatitis - symptomatic exacerbations of hepatitis
3. Cirrhosis of Liver
4. Hepatocellular Carcinoma
Hepatitis B
ACUTE CHRONIC- 5-10% <6 months (infection >6months)
Every year 1 to 2 million people die due to an infection by this virus
complications of chronic hepatitis
Endemicity
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
Global Patterns of Chronic HBV Infection
Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBsHBsAg
0 4 8 12 16 20 24 28 32 36 52 100
Acute Hepatitis B Virus Infection with RecoveryTypical Serologic
Course
Weeks after Exposure
Titre
IgM anti-HBc
Total anti-HBc
HBsAg
Acute(< 6 months)
HBeAg
Chronic(>6 months)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after Exposure
Titre
Progression to Chronic Hepatitis B Virus InfectionTypical Serologic
Course
Symptomatic Infection
Chronic Infection
Age at Infection
Chronic Infection (%)
Sym
pto
matic In
fection
(%)
Birth 1-6 months 7-12 months 1-4 years Older Childrenand Adults
0
20
40
60
80
100100
80
60
40
20
0
Outcome of Hepatitis B Virus Infection
by Age at Infection
Ch
ron
ic In
fect
ion
(%
)
Interpretation of Serologic Tests in Hepatitis B
+
Viral Hepatitis and Serology
Type of Viral Hepatitis Positive Virology
Acute HBV HBsAg, HBeAg, HBcAb IgM
Acute HBV, windows period
HBcAb IgM
Chronic active HBV HBsAg, HBeAg, HBcAb IgG
Recovery HBV HBsAb IgG, HBcAb IgG, Normal ALT
Immunized HBV HBsAb IgG
Serological Marker Hep B
1) HBsAg (Hepatitis B surface antigen):• if positive, person is infectious• Sensitivity = 0.15 ng/ml• Specificity = 99.5%
2) Anti-HBs (Antibody to HBV surface antigen):
• indicates immunity to HBV and protection from disease
• Protective level is >10 IU/ml
Serological Markers Hep B 3) Anti - HBc (Antibody to HBV core
antigen):• Total - indicates past or active
infection; present whether person is immune or chronic carrier
• Specificity = 99.8% to 99.9%• IgM - early indicator of acute
infection• No antigen test
Serological Marker Hep B 4) HBeAg (Hepatitis Be antigen):
• indicates person is highly infectious
• Selecting patients for therapy 5) Anti-HBe (Antibody to HBVe
antigen):• prognostic for resolution of infection; less infectious; spontaneous seroconversion in 10 to 20% of healthy adults per year
Serologic markers – caveats: Precore or HBeAg negative mutants:
Due to mutation in precore (abolishes HBeAg production) or core promoter region (down-regulates HBeAg production)
No effect on viral replication (may be enhanced)
More difficult to treat; greater risk of cirrhosis
Co-infection with HCV may suppress both HBeAg and HBsAg
Serologic markers – caveats: Persistent HBsAg for >6 mos = chronic
infection HBsAg and anti-HBs may co-exist in up
to 24% of chronically infected individuals; likely due to mutations in the “a” determinant of the S gene Surface antigen escape mutants described
in infants infected with HBV after HBIG + vaccination and in Liver transplants after prolonged HBIG
Anti-HBc IgM may persist for up to 2 years in 20%; chronically infected individuals may have low titres which rise during acute flares
Hepatitis B – Laboratory Tests
Serologic markers – caveats: Isolated HBcAb may be due to:
Remote infection (immune or chronic carrier)
“Window” period between HBsAg and HBsAb Co-infection with HCV False positive test result – HBcAb is marker
most prone to false positives HBV DNA may help sort this out
High ModerateLow/Not
Detectable
blood semen urineserum vaginal fluid feces
wound exudates saliva sweat
tearsbreastmilk
Concentration of Hepatitis B Virus in Various Body Fluids
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.
Hepatitis B Virus
Modes of Transmission
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 Interferon (PEGinterferon-2α) , - for HBeAg +ve
carriers with chronic active hepatitis. Response rate is 30 to 40%.
Lamivudine - a 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 and Adefovir Successful response to treatment will result in the
disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.
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.
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.
Complications Arthritis Glomerulonephritis Polyarteritis nodosa Hepatocellular carcinoma
Hepatitis D
Subviral satellite because it can propagate only in the presence of hepatitis B
coinfection superinfection
Transmission: parenteral (intravenous drug use mostly)
> 60% develop cirrhosis
HBsAg
RNA
antigen
Hepatitis D (Delta) Virus
Hepatitis D Anti-HDV Total (IgG & IgM) available Incubation time – similar to Hepatitis B High titires of HDV antibodies indicate
ongoing chronic infection Treatment same as HBV If acquired as superainfection in
chronic HBV there is in severity of infection i.e fulminant hepatitis, chronic hepatitis with rapid progression to cirhosis
Jaundice
Symptoms
ALTTotal anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
HBV - HDV SuperinfectionTypical Serologic
Course
Time after Exposure
Titre
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.
Hepatitis D - Prevention
Hepatitis C Affects each person differently No vaccine available Many people have the virus and do
not even know it By blood transfusion and IV drug
abuse Intranasal cocaine use, piercing Type 1 (most resistant) type II and
III
Incubation period: Average 6-7
wksRange 2-26 wks
Clinical illness (jaundice): 30-40% (20-30%)
Chronic hepatitis: 70%
Persistent infection: 85-100%
Immunity: No protective antibody
response identified
Hepatitis C - Clinical Features
Chronic Hepatitis C Infection
The spectrum of chronic hepatitis C infection is essentially the same as chronic hepatitis B 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, and hepatocellular carcinoma.
Waxing and waning aminotransferases (ALT/AST)
Symptoms
anti-HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Hepatitis C Virus InfectionWaxing and Waning ALT/AST
Titre
Months
Years
Time after Exposure
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
Risk Factors Associated with
Transmission of HCV
Hepatitis C Dispelling Myths
Hepatitis C is not spread by: Casual contact
Hugging/kissing Sharing eating utensils and drinking
glasses Sneezing/coughing Shaking hands Sitting on a toilet seat
Prevention
Never share drug equipment Straws, bills, needles, syringes,
water, filter, cooker, pipes etc… Never share tooth brushes/razors
or any personal hygiene articles that have blood on them (even tiny amounts).
Practice safer sex
Prevention Always make sure new & sterilized
equipment is being used for tattooing & piercing Make sure ink for tattooing is not
being shared Do not touch dirty needles without
proper equipment or following proper procedures
Laboratory Diagnosis HCV antibody - generally used to diagnose 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 monitoring the response to antiviral therapy.
HCV-antigen - an EIA for HCV antigen is available. It is used in the same capacity as HCV-RNA tests but is much easier to carry out.
Treatment Types 1 II and III
Type I is resistant than II and III
Acute HCV –alfa- interferon for 6 months also type II and III
Chronic HCV –alfa interferon+ ribavirin or peginterferon +ribavirin
Type I use alfa interferon +Ribavirin for 1 year, Telaprevir, Betapravir
HAV and HBV vaccination.
Screening of blood, organ, tissue donors
High-risk behavior modification
Blood and body fluid precautions
Prevention of Hepatitis C
Complications Cryoglobulinemia Membranoproliferative
glomerulonephritis Hepatocellular Carcinoma Cirrhosis Alfa interferon is contraindicated with
major depression and organ transplant Ribavirin contraindicated in pregnancy,
avoid for 6 months after therapy
Treatment Alcoholics should stop for 1 month
before starting treatment Screen for hepatocellular carcinoma
every 6 months Inteferon S/E: flu like syndrome
(malasia, HA, fever, myalgia) depression, myelosuppression (neutropenia, anemia)
Ribavirin S/E HA, fatigue, hemolysis
Hepatitis E Virus
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
Hepatitis E - Clinical Features
Symptoms
ALT IgG anti-HEV
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 10
11
12
13
Hepatitis E Virus InfectionTypical Serologic
Course
Titer
Weeks after Exposure
Most outbreaks associated with faecally contaminated drinking water.
Several other large epidemics have occurred since 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.
Hepatitis E - Epidemiologic
Features
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?
Prevention and Control Measures for Travelers to HEV-Endemic Regions
Hepatitis Virus – Molecular Tests Molecular assays available as follows:
Commercial assays for HBV DNA and HCV RNA In-house assays for HAV RNA & HDV RNA No molecular assay for HEV RNA
HCV RNA & HBV DNA, plasma or serum must be separated from cells within 6 hrs and plasma can be stored at 4oC for several days or -70oC for long-term
No licensed tests for diagnostic purposes; all tests are for monitoring or donor screening HCV RNA will be done in HIV or other
immunocompromised patients if requested
Nucleic Acid Amplification Tests (NAAT) for Detection of RNA/DNA Quantitation of RNA or DNA may be
reported as copies/ml or IU/ml Conversion factor for copies/ml to IU/ml is
not the same for different assays measuring the same target or different targets HBV DNA: 5.82 copies/IU HCV RNA: PCR - 2.4 copies/IU; bDNA: 5.2
copies/IU Coefficient of variation (COV) may range
from 15 to 50%
HBV DNA in Clinical Practice Routine monitoring on therapy to
assess response to treatment Every 3 months X years on oral agents Every 1 month X 6-12 on PEG/IFN
Routine monitoring off therapy to estimate prognosis and to evaluate need for treatment Every 6 –12 months normally Diagnosis of occult HBV infection