Lecture 20 Viral Hepatitis

Viral Hepatitis 

general term for liver infections/inflammation caused by hepatitis viruses that are etiologically/epidemiologically distinct 

Jaundice

most common sign of general hepatitis

yellowing of skin + eye conjunctiva caused by bile pigments in blood, accumulated due to liver damage = can’t remove bile from blood

Campaign Jaundice

common in military men

•dark urine, transient fever, nausea, and anorexia that preceded jaundice

When was the blood transmitted form of hepatitis first documented?

1885, when jaundice developed in 191 of 1,300 shipyard workers 2-8 months after receiving smallpox vaccine

•Subsequent outbreaks were traced to improperly sterilized syringes/needles, especially among patients from “VD clinics” who received injections of various therapeutic agents [Now associated with tattoos]

Infectious epidemic hepatitis was distinguished from WHAT and WHEN

serum hepatitis in 1947

Acute Self-limited Hepatitis

Hepatitis A and E

Persistent chronic hepatitis

Hep. B, C, D, F, G

How many hepatitis infections are unexplained?

15-17% of all cases, probably other viruses causing shit

Hep B History

Australian antigen due to being found in Australian aborigine, and correlated with serum hepatitis

Hep B virion

Dane Particle, name of researched from 1970

Hepadnavirus

Hep B
Unusual partly double-stranded and partly single-stranded circular DNA genome

Reverse transcriptase generates genome DNA from a pre-genome RNA within the capsid during virus assembly [like HIV]

Makes large amounts of noninfectious spherical and filamentous particles (due to overproduction of HBsAg, check pic in slide for context)

Hep B Viral Antigens

HBsAg 
>Surface antigen (Australian antigen)
>Induces protective neutralizing antibody
>Indicates past infection

HBcAg
>Core antigen
>Indicates past infection

HBeAg 
>Endogenous DNA polymerase (reverse transcriptase)
>Correlates with virus replication
>May indicate chronic / carrier state

Most people who die from hep B are due to …

•acute or chronic consequences of hepatitis B, mostly from cirrhosis (scarring of the liver) or hepatocellular carcinoma (primary liver cancer)

Of all cases in the US, 23% are what type of infections?

Sexually Transmitted Infections

Hep B Transmission

•Blood route
>Transfusion
>Sharing of contaminated needles (illicit drug use)
>Tattooing
>Ear piercing
>Human bites

•Sexual activities
>Anal intercourse
>Vaginal intercourse
>Oral sex (?)

•Mother to newborn
>At time of birth
>Transplancental transmission (?)
>Breast milk (?)

•Casual contact (unlike HIV-1)
>Sharing of household items (eating utensils, drinking glasses)
>Continuous close personal contact

Very present in blood serum → detected in saliva, semen, and cervical secretions

HIV vs Hep B

Concentration in blood (particles per ml)
•HIV  10^⁶ to 10^⁸
•HBV  10^⁸ to 10^¹⁰

Risk of infection (one needle-stick)
•HIV  <0.5% (if known to be HIV+)
•HBV  ~ 18% (if known to be HBV+)

Survival in clinical specimens 
•HIV  90-99% reduction in hours
•HBV  Up to 7 days

Hep B Clinical Course

The clinical course of Hepatitis B disease is extremely variable

•Inapparent subclinical: → Asymptomatic

•Anicteric hepatitis→ Symptoms w/o jaundice

•Icteric hepatitis→  Symptoms + jaundice

•Chronic hepatitis→ Carrier state

•Fulminant hepatitis→ Leads to death

Hep B Clinical Disease

•Incubation period ranges from 45-120 days

•Short prodromal (preicteric) period lasts from several days to greater than 1 week
  >Fever, fatigue, anorexia, nausea
  >Transition from feeling well to acutely ill is insidious (slow onset)
  >Severe abdominal pain and vomiting are unusual symptoms

•Icteric phase begins within 10 days after onset of initial symptoms

  > Appearance of dark golden-brown urine
  >Pale stools
  >Yellowish discoloration of skin and conjunctiva
  >Tenderness of liver that is enlarged

•Convalescent period begins ~4 months after initial exposure and jaundice subsides

Hep B predicted outcome in adults

•Subclinical or anicteric hepatitis  65-80%
•Icteric hepatitis  20-35%
•Complete recovery  90-98%
•Chronic disease    2-10%

Mortality rates
>Overall infection  0.2-0.5%
>Icteric disease only  0.5-1.5%

Hep B Chronic infection

2-10% of adult patients fail to clear virus from blood and become “carriers” of hepatitis B virus

•Potential source of virus for entire life

•Majority remain asymptomatic, although biochemical and histopathological liver abnormalities

•Some may be significantly incapacitated with fatigue, anorexia, malaise (but jaundice uncommon)

Hep B Chronic Infection Rates in ALL age groups

The likelihood of becoming a carrier varies inversely with age at which initial infection occurs …

•Adults = 2-10%

•Children <5 years = 25-50%

•Newborns =  ~90%

Hep B Antibodies

The pattern of disease can be associated with the antibody profile

•IgM Anti-HBc 
>Most sensitive for acute infection

•IgG Anti-HBs 
>Indicates past infection, neutralizing antibody + immune protection

•IgG Anti-HBc 
>Indicates past infection

•IgG Anti-HBe 
>Indicates acute infection, active virus replication + chronic (carrier) state

Hep B + Health Care Risk

•Health-care workers have a higher incidence of Hepatitis B virus infection

•Hepatitis B virus is 50-100 X more infectious than HIV-1

•The probability of Hepatitis B virus infection is far greater than the probability of HIV-1 infection

Hep B Treatment + Control

•Prophylaxis
>Hepatitis B Immune Globulin (HBIG)

•Acute infection
>No antiviral treatment available

•Chronic infection
>Interferon-a induces remission (25 – 40%)
>At least 5 reverse transcriptase inhibitors reduce HBeAg by >50%

Hep B + Hepatocellular Carcinoma + Vaccine

Liver Cancer
•A chronic carrier has 270x greater chance of developing liver cancer than the rest of the population

•In Asia, liver cancer is the #1 cancer that kills men and women between 25 – 30 years of age

•In Africa, 50% of all cancer patients have liver cancer

A vaccine that would successfully protect the world population from Hepatitis B virus infection would also reduce the incidence of liver cancer

Hep B Vaccine Phase 1 Clinical Trial

The test population for the Phase I clinical trial needed to fulfill a number of unique criteria

•A large population of at least 1000 participants to yield statistically valid results

•Participants must naturally have a high incidence of hepatitis B virus infection, be reasonably homogenous + be healthy at the outset of the clinical trial

•1,083 volunteers from gay community of Greenwich Village, New York City, who had no evidence of hepatitis B virus infection were enrolled in double-blinded study (50% received vaccine, 50% received placebo)

•Code broken 2 years later (June 1980)
>Of those receiving vaccine, 81% seroconversion after 1 injection + 96% seroconversion after 3 injections
>27% of those receiving placebo developed hepatitis B
>3.4% of those receiving vaccine developed hepatitis B (but all developed illness within 5 months after start of study)

Kept serum samples from gay population because ‘one day another disease will come and we’ll need a reference’ → HIV

Hep B Plasma-derived Vaccine

•A preparation of inactivated Dane particles purified from human carrier volunteers

•No longer produced due to fears of HIV-1 infection

•Fears unfounded since never associated with HIV/AIDS

Hep B Recombinant Vaccine

Current one

•Produced in yeast that contains the HBsAg gene → HBsAg purified from yeast

•Vaccine contains  >95% HBsAg

•Three intramuscular doses induce antibody response in  >90% of healthy adults

Who should get the Hep B vaxx?

•Health-care workers

•Morticians and embalmers

•Hemodialysis patients

•Recipients of blood-clotting factors

•Prisoners

•Illicit drug users

•Sexually active homosexual men

•Household and sexual contacts of carriers

Flaviviridae

Hep C

•8 genetically distinct genotypes of hepatitis C virus with each genotype composed of many subtypes

•Designated Genotype 1-8

•Most people are infected with a single dominant genotype, but it is possible to have more than one at the same time (mixed infection)

•Genotype 1 is the most common hepatitis C virus genotype In the United States found in ~75% of cases of hepatitis C virus infection

•Most of the remaining persons in the United States with hepatitis C virus infection are infected with Genotype 2 or Genotype 3

Hep C was originally called 

non-A, non-B hepatitis

Hep C USA statistics

•Estimated that ~50% of persons infected with hepatitis C virus may not know they are infected

•Of 100 persons who become infected with hepatitis C virus, ~55–85 will develop chronic infection (More than Hep B. no age correlation)

Hep C Transmission

•Blood route
>Transfusion
>Sharing of contaminated needles (intravenous drug use)
>Tattooing (2 to 3-fold risk of hepatitis C virus infection)

•Sexual activities ?
>An association between high-risk sexual activity (anal sex) and multiple sexual partners = development of hepatitis C infection
>no conclusive evidence that hepatitis C virus can be transmitted by   sexual activity
>Majority of evidence supports no risk for heterosexual couples with only one   sexual partners

•Mother to newborn
>Transmission of hepatitis C virus occurs in less than 10% of pregnancies
>Transmission unclear but probably occurs at time of birth
>No evidence that breast-feeding is involved in transmission, but caution advised

•Hepatitis C is not spread by casual contact such as hugging, kissing, or sharing eating or cooking utensils
>Possible transmission via personal-care items such as razors or toothbrushes

•Accidental needle-stick injury from someone known to be hepatitis C virus positive has a 1.8% chance of becoming infected

Not associated with respiratory, water-borne, or insect-related infections or via food or water

Hep C Acute Infection

•Incubation period is between 14 – 180 days

•Hepatitis C virus infection causes acute symptoms in 15% of cases

•Acute symptoms are mild and vague and include decreased appetite, fatigue, nausea, muscle/joint pain, weight loss

•Most cases are not associated with jaundice

•Rarely does acute infection result in liver failure

•Infection resolves spontaneously in 10 – 50% of cases, most often in persons who are young and female

•Infection associated with 4 – 5 deaths per 100,000 persons

Hep C Chronic Infection

•Approximately 80% of those infected with hepatitis C virus will develop chronic infection (the presence of detectable virus replication for at least 6 months)

•Most experience minimal or no symptoms during the initial few decades of infection

•Chronic hepatitis C virus infection can be associated with fatigue

•Chronic hepatitis C virus infection after several years my cause cirrhosis or liver cancer

Hep C Acute Infection Treatment

•Most persons who have acute infection do not receive treatment because they do not know they are infected

•For many years, a combination of interferon-a and ribavirin was used to treat hepatitis C virus infection (6 – 12 months)

•New class of drugs called Direct-Acting Antivirals (DDAs) now used that are highly effective in clearing the virus in > 90%

•Tablets must be taken for 8 – 12 weeks

Hep C Chronic Infection Treatment

Several antiviral drugs are available that are used in different combinations and for different durations depending on the genotype of hepatitis C virus infection
Mechanism of action is at the level of virus assembly (protease inhibitors)

•Harvoni: Combination of two protease inhibitors proven to cure 96 – 99% of adults with 12 weeks of therapy who have Genotype 1, 4, 5, or 6 virus 

•Epclusa: Combination of two protease inhibitors proven to cure 98% of adults with 12 weeks of therapy who have Genotypes 1-6 virus 

•Sovaldi: One protease inhibitor used in combination with interferon and ribavirin to cure 30-97% of adults with 12 or 24 weeks of therapy who have Genotypes 1, 2, 3, and 4 virus

 

Hep C Vaccine

No Vaxx because

1. 8 distinct genotypes with many subtypes

2. Chimpanzees used to be used for research, but ethical concerns = no more chimps used = no more research

Hep A USA Stats

•~4,000 new cases of hepatitis A virus infections in 2016

•Hepatitis A virus infection rarely is the cause of death

•Not a sexually transmitted infection

•No chronic infections (no carriers)

Picornavirus

Hep A

Hep A transmission

•Poor sanitation

•Consumption of contamination of water or milk

•Consumption of contaminated raw oysters or clams

•Blood transfusion (although uncommon)

NOT kissing, sex, cigarette sharing, utensil/household item sharing

Hep A Clinical Disease

•Incubation period ranges from 12 - 50 days (average = 28 days)
>Greater viral dose =shorter incubation period
>Patient remains asymptomatic despite active virus replication in gut
>Patient is most infectious due to high concentration of virus in feces

•A short preicteric phase lasts several days to more than one week
>Fever, anorexia, fatigue, malaise, nausea, vomiting
>Transition from feeling well to being acutely ill occurs abruptly
>Transient viremia is associated with low levels of virus in saliva

•Icteric phase begins within 10 days of initial clinical symptoms
>Appearance of dark, golden-brown urine (but no virus in urine)
>Followed days later by pale stools and jaundice
>Liver may become enlarged

•Convalescent period begins ~7 weeks after initial exposure
>Symptoms of jaundice subsides
>Overall outcome is age-dependent

Hep A Predicted Outcomes

•Children <5 years of age have milder cases than adults
>80-95% of children remain asymptomatic
>10 - 15% of adults remain asymptomatic

•Complete recovery is usually the rule in all age groups

•Chronic disease has not been observed (no carrier state)

Mortality rates

  >Less than 14 years of age = 0.1%

  >15 - 39 years of age = 0.3%

  >Greater than 40 years of age = 2.1%

  >Over 70% of deaths in patients >49 years of age

Hep A Diagnosis

•Biochemical assessment of liver functions
>Measurement of various proteins in serum as indicators of cellular damage of liver
>Not specific of hepatitis caused by hepatitis A virus

•Detection of hepatitis A virus-specific antibodies
>IgM anti-HAV (peaks at ~6 weeks after exposure, then drops)
>IgG anti-HAV (peaks at ~8 weeks after exposure, remains constant)

 

Hep A Treatment + Vaccine

•Passive administration of human HAV immune globulin
>Prophylactic value greatest (80 - 90%) when given early in   incubation period, then declines thereafter
>Still effective when given up to 6 days prior to onset of illness
>Not practical when repeated exposures to virus anticipated

•No antiviral drugs available

•Vaccination is mainstay for prevention of hepatitis A virus infection
>Two killed vaccines available (Vaqta and Havrix)
>Both provide 97 - 100% seroconversion within 1 month of first dose
>First dose should be given 4 weeks before travel to endemic areas