Viral Hepatitis

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Viral Hepatitis

• Therapeutics

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Hepatitis- Description

• Inflammation of the liver
• Acute viral hepatitis
• Most common cause
• Viral infection accounts gt 1/2 cases of acute
  hepatitis
• Types of Infectious Viral Hepatitis
• A
• B
• C
• D
• E
• G

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Hepatitis- Description

• Other possible causes
• Drugs (alcohol)
• Chemicals
• Autoimmune liver disease
• Metabolic diseases
• Viruses

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Epidemiology of Viral Hepatitis

• HAV is the most common cause of acute hepatitis
• HCV is the most common cause of chronic
  hepatitis.
• See Table 1

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Clinical Manifestations

• 1-Preicteric phase
• Precedes jaundice
• Lasts from 1 to 21 days
• Period of maximal infectivity for hepatitis A
• Anorexia
• Nausea
• Abdominal discomfort
• Right upper quadrant

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Clinical Manifestations

• -Preicteric phase
• Vomiting
• Constipation
• Diarrhea
• Malaise
• Headache
• Low-grade fever
• Arthralgias
• Skin rashes

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Clinical Manifestations

• 2-Icteric phase
• Lasts 2 to 4 weeks
• Characterized by jaundice
• Pruritus
• 3-Posticteric phase
• Begins as jaundice is disappearing
• Lasts weeks to months
• Malaise
• Easy fatigability

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Complications

• Most patients with acute viral hepatitis recover
  completely with no complications
• Overall mortality rate lt 1
• Fulminant hepatic failure FHF
• Chronic hepatitis
• Cirrhosis
• Hepatocellular carcinoma HCC

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Diagnostic Studies

• Transaminases (ALT, AST)
• Alkaline phosphatase
• Serum proteins
• Serum bilirubin
• Urinary bilirubin
• Prothrombin time
• Biopsy
• Physical assessment
• Splenomegaly
• Palpable liver
• Serology

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Treatment

• No specific treatment or therapy for acute viral
  hepatitis
• Most patients can be managed at home
• Drug Therapy
• No specific drug therapies
• Supportive therapy
• antiemetics
• diphenhydramine (Benadryl)
• chloral hydrate

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Hepatitis A (HAV)

• Infectious Hepatitis
• Picornavirus family (RNA)-cytopathic
• More common in developing countries
• Travelers
• Frequently occurs in small outbreaks

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Clinical Features of HAV

• Fecal-oral (food, water) route of transmission
• Found in feces 2 or more weeks before the onset
  of symptoms and up to 1 week after the onset of
  jaundice
• Present in the blood only briefly
• 2-4 weeks incubation

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Clinical Manifestations of HAV

• Acute onset
• Mild flu-like manifestations
• More severe higher mortality in
• adult gt children
• Typical cases?several weeks of malaise, anorexia,
  nausea, vomiting, and ? ALT/AST
• Jaundice develops in more severe cases.
• no carrier state
• Fulminant hepatic failure rare (0.14 fatal) but
  almost exclusively in gt50 y.o. age group

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Diagnosis of hepatitis A

• Anti-HAV immunoglobulin M (IgM)
• Appears in the serum as the stool becomes
  negative for the virus
• Detection of IgM anti-HAV indicates acute
  hepatitis
• disappears several months after the initial
  infection
• Anti-HAV immunoglobulin G (IgG)
• IgG anti-HAV is an indicator of past infection
• Presence of IgG antibody provides lifelong
  immunity

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Treatment of acute of HAV Infection

• Treatment is supportive
• no antiviral therapy available.
• Hospitalization for patients with nausea and
  vomiting ?dehydration.
• Patients with acute liver failure require close
  monitoring to ensure they do not develop FHF

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Control of Hepatitis A-Vaccine

• Active Immunity
• Two-dose vaccine (HAVRIX or VAQTA)
• -adults every 6-12 months
• -peds3 doses (0,1,6-12mo.)
• Especially For
• International travelers to endemic regions.
• Where endemicity rates are high (high-risk sexual
  activity, IV drug abusers, developmentally
  challenged, daycare employees, lab workers,
  handlers of primates, any patient with chronic
  liver disease)

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Hepatitis A Vaccine

• Combination vaccine-AB (Twinex)
• Typical administration involves 3 injections of
  1 mL IM on a 0-, 1-, and 6-month schedule.
• FDA approved for use in adults only

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Control of Hepatitis A- IG

• Passive immunotherapy with IgG
• 1-Pre-exposure
• 0.02 mL/kg IM for individuals who anticipate
  spending lt 3 months in an endemic region.
• 0.06 mL/kg IM every 4-6 months if they are
  planning to spend gt 3 months in a region where
  HAV is endemic

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Control of Hepatitis A- IG

• Passive immunotherapy with IgG
• 2-Post-exposure
• 0.02 mL/kg, given IM as a single dose.

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Hepatitis B

• Serum Hepatitis
• DNA- Virus
• Incubation period 45-180 days
• Higher risk of developing HCC

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Transmission of HBV

• Perinatal
• Sexual
• Parenteral

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High Risk Groups For HBV

• Adolescents.
• Residents / staff of homes for devel. challenged
• Hemodialysis patients
• Factor conc. recipients
• Household members/ sex partners of HBV carriers
• Travelers (gt 6 mo., endemic, close with locals)
• Travelers (short-term if med. setting)
• IVDA
• Prisoners

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Clinical Manifestations

• Insidious onset
• Symptoms more severe
• Fewer GI symptoms
• the clinical illness associated with acute HBV
  infection may range from mild to severe (lt1
  FHF).
• After acute hepatitis resolves
• 95 of adult 5-10 of infants develop anti-HBV
  antibody, clear HBsAg and HBV virions, and fully
  recover.
• 5 of adult and 90-95 of infants develop chronic
  infection.

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Inactive Carrier State

• 70-90 of HBsAg carriers ? inactive carrier state
  
• Have no symptoms, WNL LFTs, and normal or
  minimally abnormal liver biopsy results.
• Evidence of HBV replication nonexistent or
  minimal,(serum HBV DNA of 0-30,000 copies/ml)
• Remain infectious to others through parenteral or
  sexual transmission.
• Ultimately develop HBsAb and clear the virus.
• Some develop chronic hepatitis
• Remain at low risk for HCC.
• no effective antiviral therapies are available

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Chronic Hepatitis

• 10-30 of HBsAg carriers develop chronic
  hepatitis.
• Often symptomatic. most commonly with Fatigue
• May occasionally experience acute flare of
  disease, similar to acute hepatitis.
• May have extrahepatic manifestations, including
  polyarteritis nodosa, cryoglobulinemia, and
  glomerulonephritis.
• Have abnormal LFTs, evidence for active HBV
  replication, and inflammatory or fibrotic
  activity on liver biopsy.
• May be considered either HBeAg-positive or
  HBeAg-negative.
• Approximately 20 develop cirrhosis or HCC.

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Diagnosis of acute HBV infection

• HBsAg
• The 1st serum marker
• Represents presence of HBV virions in the blood.
• does not indicate whether the infection is acute
  or chronic.
• may remain detectable for life
• Individuals with HBsAg ? carriers of HBV
• Inactive carriers
• chronic hepatitis.
• HBeAg and HBV DNA ?a state of active viral
  replication and a high level of infectivity.

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Diagnosis of acute HBV infection

• Anti-HBc (HBcAb).
• The 1st antibody to appear
• Initially, IgM ? diagnostic for acute infection.
• later, IgM disappears ? IgG anti-HBc appears and
  indicates a patient has been infected with HBV
• Remain in patients who recover and in
  persistent infection

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Diagnosis of acute HBV infection

• Anti-HBc (HBcAb).
• anti-HBc (total) with a negative HBsAg and a
  negative anti-HBs indicates 1 of 4 things.
• the test result is a false positive.
• the patient is in a "window period" of acute
  hepatitis, between the elimination of HBsAg and
  the appearance of anti-HBs. not observed in
  patients with chronic infection.
• the patient has cleared the HBV virus but has
  lost anti-HBs over the years.
• the patient is one of the uncommon individuals
  with active HBV replication -ve for HBsAg
  diagnosed when either a HBeAg or HBV DNA

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Diagnosis of acute HBV infection

• Anti-HBs
• believed to offer immunity to future exposures
  to HBV.
• may persist for the life of the patient.
• HBeAg
• a marker of viral replication
• disappears when viral replication slows anti-HBe
  is detected. Anti-HBe may persist for years

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Summary of HBV Markers
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Summary of HBV Markers
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Control of HBV -Vaccine

• 1-Pre-exposure Vaccination
• Infants/children, at anterolateral thighs
• 2-3 doses
• Form 11-20 y.o. at 2,4,6 months
• from Birth, at 1-2, 6-18 months
• Adults, at Deltoid (3 doses)
• 0,1,6 months (or 0,2,12 months)
• use high dose vaccine in immunosupp., dialysis,
  severe liver disease
• boost when level lt 10mIU/mL on annual testing

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Markers after vaccination for HBV

• gt 90 of recipients develop protective
• anti-HBs.
• Vaccine recipients are not positive for
• anti-HBc unless previously infected with HBV.

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Control of HBV -Vaccine

• 2-Post-Exposure HBV Prophylaxis
• Risk of acquisition
• 20-66 from needle-stick injury
• 90 mother ? child
• HBV vaccine series HBIG 0.06 ml/kg
• May not need HBIG to prevent perinatal
  transmission (only vaccine) if mother is HBeAg
  ve.

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Control of HBV -IG

• Hepatitis B Immune Globulin
• Hepatitis B immune globulin (HBIG) derived from
  plasma.
• Provides passive immunization for individuals
  with recent exposure to a patient infected with
  HBV.
• Also administered following liver transplantation
  to persons infected with HBV to prevent
  HBV-induced damage to the liver allograft.

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HBIG vaccination Perinatal exposure
HBIG vaccination Sexual contact with an acutely infected patient
HBIG vaccination Household contact with an acutely infected person resulting in known exposure
HBIG vaccination Infant (lt12 mo) primarily cared for by an acutely infected patient
HBIG vaccination Inadvertent percutaneous or permucosal exposure
None Household contact with an acutely infected patient
Vaccination Sexual contact with a chronic carrier
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Treatment of Chronic HBV

• When to Treat?
• Candidates for antiviral therapy must have
  evidence of active HBV infection
• HBV DNA gt 105 copies/mL in patients who are
  positive for HBeAg
• HBV DNA gt 104 copies/mL in patients who are
  negative for HBeAg
• Seropositive for HBsAg gt 6mo
• Increased AST/ALT

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Treatment of Chronic HBV

• Goal of antiviral treatment
• inhibition of viral replication? loss of HBeAg
  and HBV DNA
• Secondary goals
• reduce symptoms
• prevent or delay the progression of chronic
  hepatitis to cirrhosis or HCC.
• Antiviral therapy infrequently leads to viral
  eradication
• No antiviral therapy is available for inactive
  carriers who do not have actively replicating
  virus.

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Treatment response criteria
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Predictors of Response
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Treatment of Chronic HBV

• Interferon alfa
• INF have antiviral and immunomodulatory effects.
• ? ALT is common 8-12 weeks after starting therapy
  ? INF-induced activation of the cell-mediated
  immune system.
• Loss of HBeAg and HBV DNA occurs in 37 of
  patients.
• INF is most effective when
• administered shortly after exposure
• when it is used in patients with an ALT gt 100 U/L
  who do not have a markedly elevated level of HBV
  DNA.

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Treatment of Chronic HBV

• Interferon is less effective in patients with
• (1) lifelong HBV infection,
• (2) a low ALT level (ie, lt100 U/L),
• (3) a high HBV DNA level,
• (4) end-stage renal disease,
• (5) HIV infection,
• (6) a need for immunosuppressive therapy

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Treatment of Chronic HBV

• Adverse Effects of INF
• Common but lead to discontinuation of the drug in
  only 5-10 of patients.
• Flu like symptoms (fatigue, fever, headache,
  myalgia, arthralgia),
• Neuropsychiatric symptoms (depression,
  irritability, somnolence),
• Hematological effects (granulocytopenia,
  thrombocytopenia),
• Miscellaneous effects (pain at injection site,
  dyspepsia, alopecia, thyroid function
  abnormalities).

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Treatment of Chronic HBV

• 1-INF Alpha- (2b) Monotherapy
• Adults 5mU qd or 10 mU 3/w x 4-8 months
• Children 6mU/sq.m. BSA 3/w x 4-8 months
• Pegylated INF alfa may also be used once per week
  by S/c.
• Dont use if decompensated liver dis.
• If doesnt respond to course of IFN alone
• retreat,? IFN riba , IFN lami, IFN adef, lami
  alone , adef alone

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2-Lamivudine for Chronic HB

• Lamivudine is a synthetic nucleoside analogue
  inhibits DNA polymeraseassociated reverse
  transcriptase and can suppress HBV replication.
• Treatment with 100 mg/d po for 1 year ? loss of
  HBsAg in 32 of patients.
• Histological improvement and a statistically
  significant ? in the rate of development of
  hepatic fibrosis.

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Treatment of Chronic HBV

• Advantages of Lamivudine for Chronic HB
• Ease of use and low risk of ADR
• Effective in non-responders to INF (high HBV DNA
  levels).
• Successful in decompensated cirrhosis and
  recurrent hepatitis B after liver
  transplantation.
• Disadvantages
• 24 of patients who initially responded develop
  resistance within 1st year of therapy.
• Incidence ? to 69 after 5 years of therapy.
• Due to development of a mutation in the HBV DNA
  polymerase gene.
• Resistance may also lead to a reversion of
  improvements seen on liver biopsy specimens

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Treatment of Chronic HBV

• Lamivudine Monotherapy
• Adults 100 mg qd (HIV-), 150 bid (HIV)
• Children 3mg/kg/d
• Adjust for CrCl lt 50mL/min
• Well-tolerated
• Rebound in viral replication after early
  withdrawal
• Treat for 6 months after becomes anti-Hbe
  positive

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3-Adefovir for chronic HB

• Adefovir dipivoxil is a synthetic nucleotide
  analogue.
• It inhibits HBV DNA polymerase ? DNA chain
  termination after incorporation into viral DNA.
• Patients with HBV DNA and ve HBeAg
• achieved -ve HBV DNA in 21 after 48 weeks.
• ? to 46 after 72 weeks
• Patients with HBV DNA and -ve HBeAg
• achieved -ve HBV DNA e in 69 by 48 weeks
• 71 of patients by 96 weeks.

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Adefovir dipivoxil for chronic HB

• Most treated patients experienced improvements in
  both ALT levels and liver histology findings.
  Regardless of whether they were ve or -ve for
  HBeAg
• Resistance mutations develop in lt 2 of patients
  taking long-term therapy
• Also useful in patients who developed resistance
  to lamivudine.
• Substitution for lamivudine produces a 3-log10 ?
  in HBV DNA copies /ml.

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Adefovir for chronic HB

• Monotherapy
• Adults 10 mg qd (no peds dosing yet)
• Adjust for Cr Cl lt50 ml/min
• Nephrotoxic (pre-existing CRF, on other
  nephrotoxins)
• Rebound in viral replication after early
  withdrawal
• Treatment duration as per lami

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4- Entecavir

• For lamivudine naïve HBeAg negative or positive
  patients , entecavir showed higher efficacy than
  lamivudine
• For lamivudine refractory HBeAg positive chronic
  HBV

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Hepatitis C Virus (HCV)

• Non-A, Non-B hepatitis
• has profound genetic variability throughout the
  world? 6 major genotypes and gt 80 subtypes.
• Flavi-like virus (RNA) 1988
• Genotypes 1b and 1a (common in USA) less
  responsive to INF therapy than other HCV
  genotypes.
• The genetic variability hampers efforts to design
  an effective vaccine.
• HCV is prevalent in 0.5-2 of populations in
  nations around the world

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Epidemiology of HCV

• 85 cases ? chronic
• Chronic hepatitis
• Cirrhosis (hepatic failure)
• Primary liver cancer
• Diagnosis
• Anti-HCV (ELISA ? RIBA)
• HCV RNA by PCR (response to therapy)

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Epidemiology of HCV

• Transmission of HCV
• via blood Transfusion
• via IV and intranasal drug use
• via occupational exposure
• via sexual contact
• via perinatal transmission

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Clinical Features of acute HCV

• Most cases of acute HCV are asymptomatic.
• Incubation period of 4-20 weeks, Avg 8 weeks
• Mild subclinical course usually-40-75
• aminotransferase levels rarely higher than 1000
  U/L.
• High rate of persistence
• Fulminant hepatic failure rare

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Chronic Hepatitis C

• Factors Promoting Progression or Severity
• Increased alcohol intake
• Age gt 40 years at time of infection
• HIV co-infection
• ?Other
• Male gender
• Other co-infections (e.g., HBV)

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Serologic Pattern of Acute HCV Infection with
Recovery
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal
6
1
2
3
4
0
1
2
3
4
5
Years
Months
Time after Exposure
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Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal
6
1
2
3
4
0
1
2
3
4
5
Years
Months
Time after Exposure
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Diagnosis using HCV RNA

• HCV RNA confirm the presence of active infection.
  
• It aids in the diagnosis of
• (1) early cases of HCV infection, prior to the
  development of HCV antibody or ? ALT .
• (2) seronegative cases, such as in ESRD
• (3) cases of perinatal transmission.

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Diagnosis using liver biopsy

• Can confirm the diagnosis
• Can exclude diseases that might have an impact on
  antiviral therapy, such as autoimmune hepatitis
  or hemochromatosis.
• most reliable assessment of the severity
• Knowledge of the severity influence the
  aggressiveness of therapy.

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Prevention of HCV

• NO vaccination
• Immune serum globulin or INF post-exposure ? no
  benefit
• Screen blood products anti-HCV, ALT, HBcAb
• Autotransfusion (bank blood for elective surgery)

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When to Treat Chronic HCV

• Seropositive for anti-HCV antibody gt6 months
• Seropositive for HCV RNA
• Increased AST/ALT

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Treatment of HCV infection

• Goals of Antiviral therapy
• to decrease viral replication or eradicate HCV
• (2) to prevent progression of disease
• (3) to decrease the prevalence of cirrhosis
• (4) to decrease the frequency of HCC as a
  complication of cirrhosis
• (5) to ameliorate symptoms such as fatigue and
  joint pain
• (6) to treat extrahepatic complications of HCV
  infection such as cryoglobulinemia or
  glomerulonephritis.

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Agents FDA approved for HCV

1. Interferon alfa-2b (Intron )
2. Interferon alfa-2a (Roferon)
3. Consensus interferon, which is also known as
   interferon alfacon-1 (Infergen)
4. Ribavirin, which is used in combination with
   interferon (Rebetol)

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Pegylated Interferon

• .
• pegylated INF alfa-2b and pegylated INF alfa-2a
• Other INFs under study include
• interferon beta,
• interferon gamma,
• natural interferon.

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Treatment of acute hepatitis C

• Acute hepatitis C is infrequently detected
• When identified, early therapy with interferon
  should be considered.
• In recent study, 44 patients with acute hepatitis
  C were treated with INF alfa-2b at 5 million U/d
  S/C for 4 weeks and then 3 times /week for 20
  weeks.
• 98 of patients developed a sustained virologic
  response
• SVR undetectable level of serum HCV RNA).

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Treatment of chronic hepatitis C

• INF alfa-2b, INF alfa-2a ,and consensus INF ?
  11-12 chance of obtaining a SVR.
• Combination of ribavirin with INF significantly
  improved patients' responses to treatment.
• SVR
• INF alfa-2b alone after 48 weeks 13
• INF alfa-2b plus ribavirin after 48 weeks 38.

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INFs

• HCV RNA levels are rechecked q 3 months.
• If treatment cannot induce a 102 drop in the
  viral load from baseline by week 12, the chance
  of achieving a SVR lt 3.
• ? discontinuation of therapy in such patients.
• Studies of pegylated INF alfa-2b and ribavirin
• 42 SVR in genotype 1 treated for 48 weeks.
• 82 SVR in genotypes 2 and 3.
• Studies of Pegylated INF alfa-2a and ribavirin.
• 46 SVR in genotype 1 treated for 48 weeks.
• 76 SVR in genotype 2 and 3.

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Factors Predictive of a SVR

• (1) genotype 2 or 3.
• (2) a baseline HCV RNA lt 800,000 IU/mL or lt 2 M
  copies/mL,
• (3) compliance with treatment -(4) absence of
  cirrhosis.
• INF therapy appears beneficial even in patients
  who do not have a SVR.
• patients treated with INF regardless of whether
  they achieved a SVR were at lower risk of
  cirrhosis and HCC as compared to untreated
  patients.

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Re-treatment of Non-responders to Antiviral
Therapy

• Nonresponsive to INF ribavirin, 11 achieve a
  SVR when treated with pegylated INF ribavirin.
• Nonresponders to pegylated INF ribavirin
  ?maintenance therapy with pegylated INF if they
  fulfill 2 criteria.
• 1-The presence of advanced fibrosis (eg, stage 3
  or 4 fibrosis),
• 2- a history of some reduction in viral load when
  previously treated with INF.

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Control of Chronic HCV

• Interferon side effects
• As in HBV
• Ribavirin commonly produces a hemolytic anemia

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Frequency of side effects in patients with chronic HCV treated with IFN Frequency of side effects in patients with chronic HCV treated with IFN
Side Effect of Patients
Flu-like Sx fever, headache, chills, myalgia, fatigue 60-80
GI disorders nausea, anorexia, diarrhea 15-25
Neuropsychiatric depression, irritability 10-30
Skin alopecia, pruritus, rash, dry skin 5-15
Bone marrow hypoplasia requiring dose modification, anemia, neutropenia 10-20
Cardiovascular arrhythmia, cardiomyopathy, CHF, angina lt5
Endocrine exacerbation of DM, hypo or hyperthyroidism, gynecomastia lt5
Liver and biliary liver failure/encephalopathy, jaundice lt5
Musculoskeletal arthritis, leg cramps, muscle weakness lt5
Reproductive amenorrhea, impotence, uterine bleeding lt5
Other respiratory, urinary, vision disturbances, hearing loss lt5
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HCV Treatment Follow-up

• Ribavirin
• CBC
• differential q wk in first several mo. then
  decrease to monthly
• LFTs monthly
• Thyroid fx tests q3 mo. (IFN)
• HCV RNA monthly

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Laboratory monitoring for anti-HCV therapy Laboratory monitoring for anti-HCV therapy Laboratory monitoring for anti-HCV therapy Laboratory monitoring for anti-HCV therapy Laboratory monitoring for anti-HCV therapy Laboratory monitoring for anti-HCV therapy Laboratory monitoring for anti-HCV therapy
    Baseline Wk 12 During Tx 6M/End Tx Q Mx 6 M PostTx 6 M After Tx Compt.n
Pregnancy X X X
HCV RNA X X X X
Hemoglobin X X X
CBC/DIFF X X X
WBC X X X
Platelets X X X
ALT/AST X X
TSH X   Every 12 weeks
At discretion of physician, if clinically appropriate At discretion of physician, if clinically appropriate At discretion of physician, if clinically appropriate At discretion of physician, if clinically appropriate At discretion of physician, if clinically appropriate At discretion of physician, if clinically appropriate At discretion of physician, if clinically appropriate

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