Viral Hepatitis

Virus Hepatitis A (HAV) Hepatitis B (HBV) Hepatitis C (HCV)

Family Picornaviridiae Hepadnavirdae Flaviviridae
Nucleic Acid ssRNA ​ (positive polarity) dsDNA (incomplete circular) ssRNA ​ (positive polarity)
Envelope? non-enveloped enveloped enveloped
Shape icosahedral capsid icosahedral capsid
Source of Infection Primarily fecal Blood & body fluids Blood & body fluids
Transmission Fecal-oral & sexual. Percutaneous, sexual contact & perinatal. Percutaneous, sexual contact & perinatal.
Fecal-oral transmission most Transmitted primarily by blood & sexual contact Primarily transmitted by blood and blood
common ​(food/water contamination), (heterosexual ~40% & homosexual ~10%).​ Parenteral products: ​hemophiliacs 87% and IV drug users
but also sex and drug use: transmission (rare): IV drug use, tattooing, & blood 79% (presently represent >50% of new HCV
same household ~14%, MSM ~10%, products. ​Vertical transmission​ (viremic mother to infections/yr in USA).
day care associated ~8%, IV drug abuse neonate during birth; ​NOT transplacental​) ​uncommon in Also transmitted sexually:​ sex <50 partners
~6%, international travel ~5%. USA, most common in SE Asia​.​ ​Very high concentrations 8%, sex >50 partners 9%, gay men, general
in blood, serum, & would exudates. Also present in population ~2%.
moderate concentrations in semen, vagina fluid & saliva.
Too low to be transmitted by: urine, feces, sweat, tears, &
breastmilk.
Replication Cycle Virus replicates inside the cell and ​ of No ​in vitro cell culture growth. Genome cloned
Unique replication cycle - ​does not complete replication
releases in a "burst." second strand of DNA. ​HBV is a distant relative of HIV & & sequenced. Used to develop serological &
uses reverse transcriptase​ during replication. ​ ​Seen as PCR diagnostic tests. Single open reading
two different forms in the blood: whole virus ​“Dane frame with proteolytic processing (​expressed
particle”​ (complete replicative capable virus) and long in one big polyprotein​).
rods & small particles called ​“Australian antigen”​ (just the
envelope viral proteins; ​contains HbsAg but not DNA or
core antigens​). Vastly more rods & particles (which soak
up and occupy the immune response) than whole virus.
Chronic Infection No Yes YES
Incidence Incidence ​decreasing​ in USA for past 20 Incidence has ​decreased​ dramatically in past 30 yrs in Incidence has been ​gradually increasing​ in
yrs. ​0 chronic infections​. USA; <2% of US population. ​12,400 reported chronic USA in the last 5-6 yrs; ​62,863 reported
Low prevalence in US compared to rest cases​ (~1 million estimated total chronic cases). Most chronic cases ​(~3.5 million estimated chronic
of the world, but ​~30% of US population frequent in Africa, SE Asia, Native Alaskans, and parts of cases). Incidence of acute HCV highest in
is HAV Ab+​. South America. 20-29 yr olds and 30-39 yr olds. Much more
prevalent worldwide than HBV.
Treatment No specific antimicrobials - supportive Some HIV reverse transcriptase inhibitors effective Anti-HCV drugs ​(drug resistance in HCV
treatment only. against HBV. ​ Resistance is a problem with prolonged tx. occurs more rapidly than in HBV & HIV)
Less problems with drug resistance​:​ Adefovir (high dose
nephrotoxicity), ​Entecavir​, ​Tenofovir​, ​Telbivudine​.
Prevention Active and passive immunization Active and passive immunization NO ACTIVE OR PASSIVE IMMUNIZATION
Safe sex. Screening of blood for transfusions. Screening of blood used for transfusions.
Avoid IV drug abuse & needle sticks. Modification of high risk behaviors.
 Hepatitis: inflammation and damage of the liver
● Many causes such as chronic alcoholism, injury, etc.
● Viral hepatitis - leading cause of liver cancer; most common reason
for liver transplants
● Incidence: 15,000 deaths/year in USA; 1.5 million deaths/year worldwide
Acute Viral Hepatitis in USA, 1983-2013
● Historical declines in incidence of HAV, HBV, & HCV due to:
○ HAV & HBV - introduction of vaccines & better drug treatment
○ HCV - blood & blood product testing
● More recently, incidence of HCV has been increasing

HAV CLINICAL INFECTION PATHOBIOLOGY OF HBV CLINICAL PRESENTATION OF HCV

Symptomatic vs.
asymptomatic infection is age
dependent. Children (most
asymptomatic), adults (~70%
symptomatic). Usually mild &
self-limiting disease.
Infrequently fatal (but risk
increases with age). ​No
chronic asymptomatic
infection. Life-long
immunity follows
resolution.
Primary infection: ​~50% symptomatic​ and ​~50% asymptomatic​. ​Majority of
individuals who become infected ​(~85-95%) resolve​ the HBV infection​ (like
HAV). ~5-15% develop chronic infection of HBV, which can be symptomatic
(~25%) or ​asymptomatic (~75%)​. ​Asymptomatic chronic carriers are
infectious​ and serve as a main reservoir of transmitting HBV. ​Symptomatic
chronic​ hepatitis leads to cirrhosis and liver failure and eventually (~30 yrs
later)​ ​hepatocellular carcinoma​ ​(~100X risk).​ ​ ​Age at exposure & route of
transmission greatly affect both asymptomatic/symptomatic %, as well as
acute/chronic %.​ ​Greater risk of symptomatic infection as you age, and
neonates more likely to develop chronic hepatitis (chronic vs. symptomatic
infection have inverse relationship).
Primary infection - incubation period is 6 wks to 2 mos. ​~80%
infected with HCV don’t know they have been infected: ​~60%
asymptomatic​ and ​~20% non-specific sx’s​.​ Only ​~20%
develop acute hepatitis​ with jaundice and cirrhosis. ​Most
HCV-infected do NOT know they have been infected and
are ​persistently colonized​, thereby becoming
asymptomatic carriers ​(can transmit the disease unknowingly
to others). ~10% exhibit symptoms of chronic hepatitis. Liver
failure occurs ​~10-20 yrs post infection.​ Clinical
consequences of chronic HCV infection: hepatitis / hepatic
fibrosis / cirrhosis, end-stage liver disease ​necessitating liver
transplantation (#1 cause in USA)​, & ​hepatocellular
carcinoma​.

Prevention of Hepatitis A: Prevention of Hepatitis B:

● Break transmission cycle - good sanitation, locate "common source" of outbreaks ● HBV ​Passive​ Immunization: Hepatitis B
● HAV ​Passive​ Immunization: Immune Globulin immunoglobulins (HBIG)
○ Pre-exposure​ for travelers to intermediate & high HAV-endemic regions ○ Un- or incomplete immunized with risk
○ Post-exposure​ (within 14 days) for household or other intimate contact with acute exposure
HAV case; also common source exposure (i.e. infected food handler) ○ Newborn of HBV-infected mother
● HAV ​Active​ Immunization: ● HBV ​Active​ Immunization:
○ Formalin-​inactivated (killed)​ virus ○ Hepatitis B surface antigen (HBsAg)
○ Safe, ~99% effective, long lasting (at least 20 years) ○ "Heptavax" - purified HBsAg
○ Routine childhood vaccination (since May 2006) ○ "Recombivax"
○ "Catch-up" vaccine recommendations (“at risk” groups): travelers to endemic areas / ■ Recombinant HBsAg produced in
military, daycare workers, homosexual & bisexual men, IV drug users, individuals w/ yeast
chronic liver disease, communities with high HAV rates (native Alaskans & Native ■ Universal immunization at birth & for
American Indians) health care workers
■ Current recommendation in USA

Clinical Diagnosis & Serology of HBV Infection:

● HBsAg​ = hepatitis B surface antigen ​(present during infection)
● Anti-HBsAg​ = antibody to hepatitis B surface antigen
● Anti-HBcAg​ = antibody to hepatitis core antigen
● Anti-HBcAg IGM​ = IgM against hepatitis core antigen
● Can test to see if these 4 are in the blood; useful for diagnosis
● HBsAg​ and​ IgM against Hep B core antigen​ seen EARLY in infection
● Typical results: ​HBsAg (+), HBeAg (+), anti-HBsAg (-)
● Anti-HBsAg​ is NOT seen early, presumably because of the “Australian particles”
● HBsAg & HBeAg​ associated with infectivity
soaking up / binding all of the antibody!
● With chronic HBV infection, you never develop antibody to surface
● Window of Infectivity: ​cannot detect either surface antigen or antibody to
antigen!
surface antigen; 8-week period where Hep B is not detectable (btw 24-32 wks)
● Typical result after 32 wks: ​HBsAg (-), Anti-HBsAg (+)​ (associated with
protection)

Treatment of Hepatitis C: Anti-HCV Drugs

● Antiviral drug targets:
○ NS3 - serine protease
○ NS5A - phosphoprotein
○ NS5B - RNA polymerase
● Pegelated interferon +/- Ribavirin ​(primary treatment 5-10 years ago)
● Serine protease inhibitors
○ 1st new drugs for hepatitis C in 20 years
○ Used in combination with​ pegelated interferon & ribavirin
○ Simeprevir​ - FDA approved in Nov 2013
● Sofosbuvir ​- FDA approved in Dec 2013
○ Inhibits RNA-dependent RNA-polymerase (NS5B)
● Harvoni (Sofosbuvir combined with Ledipasvir)
● Preicteric:​ fever, malaise, fatigue, anorexia, nausea & vomiting
○ FDA approved in October 2014
● Icteric:​ jaundice
● Incubation period is 2 weeks to 2 months ○ Ledipasvir inhibits a viral phosphoprotein (NS5A)
● Virus is at its ​highest concentration in stool ​during preicteric phase ○ Cost is controversial! Very expensive!
● Disease is most infectious / contagious before the clinical sx's appear ● Simeprevir​ plus sofosbuvir - approved Nov 2014
○ Much more cost effective