Acute Hepatitis C

1
Acute Hepatitis C

• Micah Moobery, MD
• September 26, 2007
• Morning Report

2
Overview

• Most common chronic liver disease
• Accounts for 8000-13,000 deaths/year
• Leading cause of death from liver disease
• 2.7 million people with ongoing HCV infection in
  the U.S.
• Most common cause for liver transplants in the
  U.S. and Europe
• 20,000 new cases/year (decreased from 230,000
  cases/year in 1980s)
• In 1997, the cost of Hepatitis C was
  approximately 5.46 billion (92 due to chronic
  liver disease)

3
Microbiology

• Member of the Flaviviridae family
• At least six HCV genotypes exist, with multiple
  subtypes
• Replication occurs via RNA-dependent RNA
  polymerase
• HCV genome encodes structural proteins (core
  protein envelope glycoproteins E1 and E2) and
  non-structural proteins (proteases, helicase and
  RNA-dependent RNA polymerase)
• Two regions within the E2 protein have a very
  high mutation rate, which may explain its ability
  to circumvent the immune system

4
Epidemiology

• More than 170 million people worldwide have
  chronic hepatitis C
• In the US, 1.8 of the population is seropositive
  for hepatitis C
• 75 of seropositive individuals have chronic
  infection
• Prevalence in intravenous drug users is gt50 and
  may be as high as 90
• Approx. 4 million in the US have been infected
  with hepatitis C virus, of whom 2.7 million have
  chronic infection
• In the US, hepatitis C is more prevalent in
  African-American and Hispanic populations than
  Caucasians

5
Transmission

• In the U.S., injection drug use is the chief mode
  of transmission
• Other modes of transmission include blood
  transfusions, organ transplant, exposure to an
  infected sexual partner, exposure to blood in
  health care workers and perinatal exposure
• Other possible modes of transmission tattoos,
  piercings
• Estimated risk with blood transfusion is now lt 1
  in a million per unit transfused (since 1990 when
  screening donors for Hep C antibodies was
  initiated)

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Testing

• Recommended for
• HIV infected persons
• Hemophilia who received clotting factor before
  1987
• Persons who were ever on HD
• Unexplained abnormal aminotransferase levels
• Recipients of blood transfusions or organ
  transplant before July 1992
• Children born to HCV infected mothers
• After needle stick injury or mucosal exposure to
  HCV positive blood
• Current sexual partners of HCV people

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Testing

• Usual method is to screen for Hepatitis C
  antibodies
• If antibody positive, then confirm viremia with
  HCV RNA testing
• Both quantitative and qualitative HCV RNA tests
  are available
• If quantitative test is used and is negative,
  should test with qualitative test because of its
  increased sensitivity

8
Clinical Course

• 55-85 with acute Hepatitis C infection remain
  HCV RNA
• Rate of spontaneous clearance of virus after it
  has persisted for at least 6 months is very low
• Most people with chronic infection are
  asymptomatic
• Cirrhosis occurs in up to 50 of chronically
  infected patients and usually requires passage of
  2 or more decades

9
Clinical Course

• Cirrhosis is a prerequisite for most of the major
  complications of liver failure in patients with
  chronic HCV
• Risk of developing hepatic decompensation in
  patients with cirrhosis is 3.9 per year
• Most common form of decompensation is ascites,
  followed by variceal bleeding, encephalopathy and
  jaundice
• HCV accounts for 1/3 of HCC cases in the U.S.
• Risk of developing HCC once cirrhosis has
  developed is up to 3 per year

10
Clinical Course

• Survival is generally not impaired until
  cirrhosis has developed
• With compensated cirrhosis, the 3, 5, and 10 year
  survival are 96, 91 and 79
• Once decompensated cirrhosis occurs, 5 year
  survival drops to 50
• Once complications of cirrhosis have occurred,
  liver transplantation is the only effective
  therapy
• Recurrent infection of the graft occurs in almost
  all patients, however long-term survival is the
  same as that for other causes of liver failure
  (60-80)

11
Host Factors

• HCV infection after the age of 40 to 55 may be
  associated with more rapid progression of disease
• Disease progression accelerated in HIV
• High BMI and hepatic steatosis increases risk for
  development of fibrosis
• Daily use of marijuana is associated with more
  rapid fibrosis progression
• Alcohol promotes progression of HCV and increases
  HCV replication

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Extrahepatic Manifestations

• Hematologic diseases
• Essential mixed cryoglobulinemia
• Lymphoma
• Renal disease
• MPGN
• Autoimmune disorders
• Thyroiditis
• Dermatologic conditions
• Porphyria cutanea tarda
• Lichen planus
• Diabetes mellitus

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Treatment

• Goal of treatment prevent complications
• Infection is considered eradicated when there is
  a sustained virologic response (SVR) absence of
  HCV RNA at end of tx and 6 months later
• Early virologic response (EVR) 2-log drop in
  HCV RNA 12 weeks into tx
• End of treatment response (ETR) absence of HCV
  RNA at end of tx
• Relapse HCV RNA undetectable on tx but becomes
  detected after discontinuation
• Nonresponders HCV RNA levels remain stable on
  tx
• Partial responders HCV RNA levels decline by gt
  2 logs but never become undetectable

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Treatment

• Genotype is the strongest predictor of response
• SVR rates higher in persons with genotype 2 or 3,
  lower pretreatment HCV RNA levels, younger ages,
  lower body weights and absence of bridging
  fibrosis and cirrhosis

15
Treatment

• Contraindications to Treatment
• Major uncontrolled depressive illness
• Renal, heart or lung transplant recipient
• Autoimmune hepatitis
• Untreated hyperthyroidism
• Pregnant or unwilling/unable to comply with
  adequate contraception
• Severe concurrent diseases
• Under 3 years of age
• Known hypersensitivity to tx meds

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Treatment

• Highest overall SVR has been achieved with
  combination of weekly SQ injections of long
  acting peginterferon alfa and oral ribavirin
• Peginterferons decrease renal clearance and
  increase the half life of the medication
• Genotype-1 treatment regimen is 48 weeks
• Genotype 2 3 treatment regimen is 24 weeks

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Adverse Treatment Effects

• Interferon alfa
• Neutropenia
• Thrombocytopenia
• Depression
• Hypo/hyperthyroidism
• Irritability
• Concentration and memory disturbances
• Visual disturbances
• Fatigue, muscle aches, headaches
• Nausea and vomiting
• Skin irritation
• Low grade fever
• Weigh loss, insomnia
• Hearing loss, tinnitus
• Interstitial fibrosis

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Adverse Treatment Effects

• Ribavirin
• Hemolytic anemia
• Fatigue
• Itching
• Rash
• Sinusitis
• Birth defects (must use strict contraception
  methods during treatment and for 6 months after)
• Gout

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Acute Hepatitis C

• Identification of patients with acute Hepatitis C
  infection is uncommon
• Most cases are anicteric and asymptomatic
• Accounts for 20 of cases of acute viral
  hepatitis in U.S.
• Presence of HCV RNA in serum or liver is the
  first biochemical evidence of infection
• HCV RNA is detectable in serum by PCR within days
  to 8 weeks following exposure, depending in part
  on size of inoculum
• No definitive minimal interval following
  suspected exposure after which negative PCR
  excludes infection

20
Acute Hepatitis C

• Serum aminotransferases become elevated
  approximately 6-12 weeks after exposure
• Half of patients with symptomatic acute infection
  have detectable antibodies to HCV
• Spontaneous clearing of infection occurs in
  approx 15-20 of patients (usually clear within
  12 weeks and no later than 20 weeks after onset
  of symptoms)
• Conversion is permanent in virtually all patients
• Normalization of ALT does not necessarily mean
  the infection has cleared

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Acute Hepatitis C

• Symptoms may include anorexia, nausea (34),
  malaise, RUQ pain (25), jaundice (68), dark
  urine/acholic stools (39), and flu-like symptoms
  (55)
• Illness typically lasts 2-12 weeks
• Fulminant hepatic failure with acute infection is
  rare
• Some evidence that the risk of developing chronic
  infection is lower in patients presenting with
  symptomatic acute infection

22
Acute Hepatitis C

• Treatment?
• No consensus statement
• Studies have been very heterogeneous and limited
  by small sample size, lack of randomization,
  variability in the timing, dose, schedule,
  endpoints and f/u after treatment
• Studies further hampered by fact that majority of
  people with acute Hep C infections are
  asymptomatic and furthermore by the fact that
  patients with symptoms are more likely to
  spontaneously resolve the infection

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Acute Hepatitis C

• Treatment?
• Majority of trials have used interferon alpha
  montherapy
• Clear evidence that SVR with interferon therapy
  alone is very high in acute Hepatitis C
• AASLD Recommendations
• Can delay tx for 2-4 months to see if infection
  clears spontaneously
• Despite most studies using standard interferon,
  it is reasonable to use peginterferon due to its
  ease of admin.
• No recommendations can be made re use of
  Ribavirin
• Reasonable to treat for at least 6 months

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Resources

• AASLD guideline Diagnosis, management and
  treatment of Hepatitis C
• MDConsult.com. Viral hepatitis C. Anand, Lauer,
  Sisson.
• Uptodate.com. Diagnosis and treatment of acute
  hepatitis C in adults. Lorenz, Endres.
• Uptodate.com. Clinical features and natural
  history of hepatitis C virus infection. Chopra.
• Uptodate.com. Epidemiology and transmission of
  hepatitis C virus infection. Chopra.