This was presented at the Resident and New Practitioners Forum on February 23rd and offered as a Continuing Education credit for those who attended.

1. JOY A. AWONIYI, PHARMD.
PGY1 PHARMACY PRACTICE RESIDENT
MIAMI VA HEALTHCARE SYSTEM
Annual Resident and New Practitioner
Continuing Education Forum
Saturday, February 23rd, 2013

2. Objectives
2
 To provide a brief overview of hepatitis
 To describe the anatomy and physiology of the liver
 To define hepatitis A, B and C
 To discuss the anatomy, pathophysiology, and epidemiology
of each viral hepatitis condition
 To provide an overview of drug therapy for Hepatitis A, B,C
 To discuss associated patient assessment parameters
including monitoring for efficacy and side effects of antiviral
medications
 To explain the importance of laboratory tests and interactions
used in the diagnosis and management of hepatitis
 To discuss the healthcare practitioners role in managing viral
hepatitis

3. WHAT IS HEPATITIS?
3
 Hepatitis is inflammation of the liver
 Causes of hepatitis
 Viruses
 Hepatitis A, B, C
 Heavy alcohol use
 Illicit Drugs
 Medications
 Allergic Reactions
 Obesity
 Autoimmune

4. ANATOMY AND PHYSIOLOGY OF THE LIVER
4
 Anatomy
 3 lb located on the right side
and protected by the rib cage
 Composed of a right and left
lobe
 Functions
 Filters blood from the digestive
tract
 Detoxifies chemicals and
metabolizes drugs
 Manufactures proteins
important for blood clotting
and other functions

5. Hepatic Function Tests
5
 Indicators of liver injury
 In the event of injury to the
liver, enzymes leak into circulation Lab Test Reference Range
 Aspartate Aminotransferase (AST)
 Alanine Aminotransferase (ALT)
AST 8 - 48 U/L
 Lactate Dehydrogenase (LDH) ALT 7 – 55 U/L
 Alkaline Phosphatase (ALP)
LDH 105 – 333 U/L
 Levels may be normal in cases of
chronic inflammation ALP 45 – 115 U/L
Tbili 0.2 – 1.2 mg/dL
 Indicators of liver function
 Total Bilirubin (Tbili) Albumin 3.5 – 5.0 g/dL
 Albumin PT 9.5 – 13.8 seconds
 Prothrombin Time (PT)

6. Symptoms of Viral Hepatitis
6
Fever
Gray-
colored Fatigue
stool
Abdominal Loss of
pain appetite
Vomiting Nausea

7. Hepatitis A
7

8. Etiology and Pathophysiology
8
 Caused by Hepatitis A Virus; a positive-strand, non-
enveloped virus that infects only primates
 Resistant to freezing, acid and detergents
 Survives extended periods in water and soil
 Inactivated by formalin and chlorine
 Transmitted through fecal-oral route
 Infection by person-to-person contact or ingestion of
contaminated food or water
 Higher prevalence in regions with low sanitation standards
 Not associated with chronic disease - The adaptive
immune response is effective in eliminating the virus
Hepatitis A

9. Epidemiology
9
 Incidence rate was last
Reported cases of Hepatitis A
reported as 0.5 per
declined 88% between 2000 and
100,000 population
2010
(2010)
 Risk Factors
 Men who have sex with
men
 Recent international travel
 Injection drug use
 Sexual or household
contact with an infected
person
 Involvement in a
food/waterborne
outbreak
Hepatitis A

10. Clinical Presentation
10
Incubation period  Typical Symptoms
(15-50 days)  Fever/ Malaise
 Nausea/vomiting
 Abdominal discomfort
 Jaundice
Symptom Development
 70% of children younger than 6
years are asymptomatic
Elevation of Liver Enzymes
 Physical Signs
 Tender hepatomegaly
 Splenomegaly
Symptoms and lab  Bradycardia
abnormalities resolve within
2 months
 Chronic infection does not occur
Hepatitis A

11. Treatment
11
 No medications are available for the
treatment of Hepatitis A infection
 Supportive Treatments
 Appropriate rest
 Balanced Nutrition
 Avoidance of hepatotoxins
 Acetaminophen
 Alcohol
 Patients may require hospitalization to treat
dehydration or evidence of hepatic
decomposition
 Contact precautions should be observed
during infectious period
Hepatitis A

12. Vaccination
12
Recommended for the following patient populations:
Travelers to regions
Children at 24 Men who have sex Illegal drug users
with intermittent or
months with men (both IV and non-IV)
high rates of Hep. A
Persons who work Persons who work
Persons with clotting Patients with chronic
with HAV-infected with HAV in
factor disorders liver disease
primates laboratories
Families or caregivers
of recent adoptees
Anyone else seeking
from countries were
long-term protection
Hepatitis A is
common
Hepatitis A

13. Vaccination
13
Hepatitis A  Dose
Vaccine, Inactivate  12 months -18 years – 0.5mL IM
d  19 years and older – 1mL IM
 Post-exposure: Single dose ASAP
Havrix®
 Administration
• 1440 Units/1mL
 Deltoid is preferred for patients 2 or
• Booster after more years
6-18 months  Anterolateral thigh may be used
between 12 and 23 months
 SHAKE WELL BEFORE USING!
Vaqta®
• 50 Units/1mL  Side effects
• Booster after  Injection site erythema, swelling, or pain
6-12 months  Headache, irritability, somnolence
 Fatigue, fever, malaise
Hepatitis A

14. Hepatitis B
14

15. Etiology and Pathophysiology
15
 Caused by Hepatitis B Virus, a small enveloped
animal viruses that replicates in hepatocytes
 Utilizes reverse transcription for replication
 8 recognized genotypes
 Transmitted through exposure to infectious blood or
body fluids containing blood
 Percutaneously
 Sexually
 Perinatally
 Carriers are at increased risk of developing
cirrhosis, hepatic decompensation, or
hepatocellular carcinoma
Hepatitis B

16. Viral Replication
16
Virions bind to the host cell and are
internalized by endocytosis
Covalently closed circular DNA (cccDNA)
is established in the hepatocyte nucleus
DNA Becomes integrated into the host
genome through reverse transcription
Hepatitis B surface antigens are created
within the cell
Hepatitis B

17. Disease State Terminology
17
• Hepatitis B surface antigen
HBsAg • Marker of HBV infection
• Hepatitis B e antigen
HBeAg • Marker of active viral replication
• Antibody to Hepatitis B e
Anti-Hbe • Marker of recovery
Hepatitis B

18. Disease State Terminology
18
Chronic Hepatitis B
• Chronic necroinflammatory disease of the liver caused by
persistent infection with the HBV
Inactive HBsAg Carrier state
• Persistent HBV infection without significant, ongoing
necroinflammatory disease
Resolved Hepatitis B
• Previous HBV infection of the liver without further evidence of
active infection or disease
Acute Exacerbation of Flare of Hepatitis B
• Intermittent elevations of aminotransferase activity to more than 10
times the ULN and more than twice the baseline value
Hepatitis B

19. Disease State Terminology
19
Reactivation of Hepatitis B
• Reappearance of active necroinflammatory disease in
a person known to have the inactive HBsAg carrier
state or resolved Hepatitis B
HBeAg Clearance
• Loss of HBeAg in a person who was previously positive
HBeAg Seroconversion
• Loss of HBeAg and detection of anti-HBe in a person
who was previously HBeAg positive and anti-HBe
negative
Hepatitis B

20. Epidemiology
20
CDC Surveillance Report Risk Factors
 350 - 400 million people Healthcare Hemodialysis
worldwide with Chronic workers patients
Hepatitis B
Household
 1.25 million HBV carriers in contacts or sex
partners of
Recipients of
blood products
the United States in 2010 infected persons
Patients with a
 Accounts for 4-5.5 Recent history of
sexually-
multiple sex
thousand deaths in the partners
transmitted
disease
United States yearly
 Estimated 35,000 cases of Men who have
sex with Men
IV drug users
new infections
Hepatitis B

21. Clinical Presentation
21
Incubation period  Signs/Symptoms
 Gradual onset of anorexia, malaise,
(30-180 days)
and fatigue
 Right upper quadrant pain
 Dark urine, light-colored stools
Symptom Development and  Illness resembling serum sickness
Elevation of liver enzymes
 Jaundice
 Yellowing of the skin, white of the eyes
or other body fluids
Jaundice
 Variable Course
 Rapid symptom improvement
 Prolonged disease with slow resolution
Variable Course
 Relapsing hepatitis
 Rapid progression to hepatic failure
Hepatitis B

22. Goals of Treatment
22
 Reduce viral replication to achieve remission of
liver disease
 Improve natural history of chronic infection
 Prevent cirrhosis, hepatic failure, and
hepatocellular carcinoma
Hepatitis B

23. Interferons
23
 Naturally produced proteins  Side Effects
with antiviral, antitumor, and  Flu-like symptoms
immunomodulatory actions  Cytopenia
 Depression, anxiety, irritabilit
 Options y
 Intron A (Interferon alpha-2b)  Autoimmune disorders
 Pegasys (Pegylated
interferon alpha-2a)  Contraindicated in
 Pegintron (Pegylated decompensated cirrhosis
interferon alpha-2b)
 Advantage: Resistance
 Administration does not occur
 Given as subcutaneous
injections
 Weekly for 48 weeks
Hepatitis B

24. Antiviral Agents
24
 Interfere with viral replication
and weaken or eliminate
activity
 All are administered orally
once everyday
 All should be dose adjusted
for patients with reduced
CrCl
 HBV DNA Polymerase
Inhibitors
 NRTIs: Nucleoside Reverse
Transcriptase Inhibitors
Hepatitis B

25. Antiviral Agents – Polymerase Inhibitors
25
 Adefovir (Hespera®)
 Modest potency
 Moderate resistance
 10mg/day
 Side effects:
hematuria, asthenia, hepati
tis exacerbation
 Entecavir (Baraclude®)  Telbivudine (Tyseka®)
 High potency  High potency
 Low resistance  High resistance
 0.5mg/day  600mg/day
 Side effects:  Side effects:
fatigue, headache, dizzines fatigue, creatinine kinase
s elevation, headache, diar
rhea
Hepatitis B

26. Antiviral Agents - NRTIs
26
 Lamivudine (Epivir®)  Tenofovir (Viread®)
 Moderate potency  Showed to be more
effective than adefovir
 High resistance
 High potency
 100mg/day
 Low resistance
 Side effects: Pancreatitis,
fatigue, neuropathies,  300mg/day
diarrhea  Side effects:
asthenia, diarrhea, naus
ea, pain, anorexia
Hepatitis B

27. Antiviral Agents – Not FDA Approved
27
 Emtricitabine (Emtriva®)
 NRTI
 No advantage over lamivudine
 Clevudine
 Provides sustained suppression of HBV DNA for several
months after the cessation of therapy
 Less potent in inducing suppression and seroconversion
 Approved and marketed in South Korea
Hepatitis B

28. Treatment Indications
28
HBeAg HBV DNA (IU/mL) ALT (x ULN) First Line Therapy
Positive >20,000 ≤2 Do not treat
Positive >20,000 >2 Interferon, adefovir, or entecavir
Negative >20,000 >2 Interferon, adefovir, or entecavir
Negative >2000 1 to >2 Liver biopsy
Negative ≤2000 ≤1 Observe
Either with ≥10 to 100 ≤1 to >2 Compensated: Adefovir or Entecavir
cirrhosis Decompensated: add Lamivudine
or Telbivudine; Liver transplantation
Either with <10 to 100 < 1-2 Compensated: Observe
cirrhosis
Decompensated: Liver
Transplantation
Hepatitis B

29. Combination Therapy
29
 Combination does not increase efficacy in patients
who have not received treatment
 Adding a second antiviral agent after the emergence
of resistance has been successful
 Current guidelines do not recommend combination
 Exception is made when resistance may lead to or aggravate
hepatic failure
 Examples: Decompensated cirrhosis or after liver transplantation
 In the event of drug resistance, it is recommended to
add an agent rather than switch to another antiviral
agent
Hepatitis B

30. Vaccination
30
Recommended for the following patient populations:
Older children
Susceptible sex Persons with
who have not
Infants at birth partners of multiple sex
been
infected persons partners
vaccinated
Persons with
Men who have Injection drug Persons with HIV
chronic liver
sex with men users infection
disease
Healthcare
Adults aged 19- Anyone else
workers exposed Persons with
59 with diabetes seeking long-
to blood on the ESRD
mellitus term protection
job
Hepatitis B

31. Vaccination
31
Hepatitis B Vaccine  Dosing schedule
 0-19 years: 0.5mL at 0,1, and 6 months
 20+ years: 1mL IM at 0,1, and 6 months
Engerix B®  Hemodialysis: 2mL at 0,1,2, and 6
months
• 20mcg/mL
 Administration
 Deltoid is preferred
 Anterolateral thigh preferred for
neonates/infants/small children
 DO NOT GIVE IV!
Recombivax
HB®
 Side effects
• 10mcg/1mL  Injection site pain, pruritis, erythema, or
burning
 Headache, vertigo, flushing
 Fatigue, fever, malaise
Hepatitis B

32. Vaccination
32
Twinrix ®
 For adults 19 and older
 Dose
 1mL IM at 0,1, and 6 months
 Accelerated schedule
 1mL IM on days 0,7, and 21-30
 Booster at 12 months
 Side effects:
 Soreness
 Headache
 Fatigue
Hepatitis A/B

33. Hepatitis C
33

34. Etiology and Pathophysiology
34
 Caused by Hepatitis C Virus
 Enveloped single-stranded RNA virus
 Naturally targets hepatocytes
 Transmitted of blood contaminated with HCV
 Tattooing, sharing razors or needles
 Nosocomial patient-to-patient transmission, or needle-stick
injuries to health care workers
 Organ transplantation before 1992
 Complications
 Leads to chronic hepatitis in 70 - 75% of patients
 Cirrhosis develops in 20-50% of patients
Hepatitis C

35. Viral Replication
35
Virions bind to hepatocyte receptors and are
taken up by endocytosis
Protein coat dissolves and the RNA code is
released inside the cell
The RNA takes over the cell to make viral proteins
Infected enzymes cut the protein strand into
various viral proteins, making hundreds of copies
Protein shells form around the RNA to make a new
virus and are released from the infected cell
Hepatitis C

36. Epidemiology
36
 Affects an estimated 180 million
globally
 More common among minority 15-30% of patients with chronic HCV
populations have progression to cirrhosis over the
 Associated with lower economic ensuing 30 years
status and lower education levels
 Leading cause of chronic
hepatitis, cirrhosis and liver
cancer
 Principle cause of death from
liver disease and leading
indication for liver
transplantation in the United
States
 Approximately 8-10 thousand
deaths occur as a result every
year
Hepatitis C

37. Clinical Presentation
37
 Most patients are  Extrahepatic
asymptomatic Manifestations
 Arthralgias
 Symptoms associated  Paresthesias
with complications  Myalgias
 Hepatic Encephalopathy  Pruritis*
 Altered metal status  Sicca (Sjogren) Syndrome
 Ascites  Sensory Neuropathy
 Ankle edema
 Abdominal distension
 Variceal bleeding
 Hematemesis
 Melena
Hepatitis C

38. Treatment Goals
38
Treatment Goals Therapy Options
 To achieve sustained  Interferon-based
eradication of HCV antiviral therapy
 To prevent  Protease Inhibitors
complications and
death from infection
 Liver transplantation
Hepatitis C

39. Virological Response Terminology
39
RVR • Rapid Virological Response
• HCV RNA negative at treatment week 4
EVR
•Early Virological Response
•Partial: >2 log reduction in HCV RNA level compared to baseline at
week 12
•Complete: HCV RNA negative at treatment week 12
ETR
• End-of-treatment response
• HCV RNA Negative at the end of 24 or 48 weeks of
treatment
SVR
• Sustained Virological Response
• HCV negative 24 weeks after treatment cessation
• Associated with permanent cure in the majority of patients
Hepatitis C

40. Disease-State Terminology
40
Breakthrough Relapse
• Reappearance of HCV RNA in serum while still on therapy
Non-responder
• Individual with failure to clear HCV RNA from serum after 24
weeks of therapy
Null Responder
• Individual with failure to decrease HCV RNA by <2logs after 24
weeks of therapy
Partial Responder
• Two log decrease in HCV RNA but still HCV RNA positive at week
24
Hepatitis C

41. Interferon-based Antiviral Therapy
41
 Currently recommended therapy for chronic HCV
infection
 Peginterferon Alpha 2a/b (PegIntron®, Pegasys® )
 Administered subcutaneously every week
 Dose adjusted for neutropenia and/or thrombocytopenia
 Dose adjusted for renal impairment
 Ribavirin (Rebetol®, Ribasphere®, others)
 Daily oral administration
 Addition provides a significant decrease in relapse rate
compared to interferon alone
 Dose adjusted for renal impairment
Hepatitis C

42. Interferon-based Antiviral Therapy
42
Hepatitis C

43. Interferon-based Antiviral Therapy
43
Adverse Events Contraindications
 Pregnancy
 Many patients discontinued
trials due to side effects
 Autoimmune conditions, may be
exacerbated by Pegylated
 Influenza-like effects: interferon
fatigue, headache, fever, rigo
rs (>50%)  Major uncontrolled depression or
suicidal ideation
 Psychiatric effects:
Depression, irritability, insomnia  Age less than 2 years
(22-31%)
 Hypersensitivity
 Laboratory Abnormalities
requiring dose reduction  Solid organ transplantation
 Neutropenia (18-20%)
 Anemia  Untreated Thyroid disease
 Hemolytic anemia with ribavirin
Hepatitis C

44. Interferon-based Antiviral Therapy
44
DOSE REDUCTIONS
Hepatitis C

45. Interferon-based Antiviral Therapy
45
DOSE REDUCTIONS
Hepatitis C

46. Response Predictors
46
 Likelihood of SVR is lower
with patients with a high
pretreatment HCV RNA
level
 >600,000 IU/mL
 Likelihood of SVR is higher
among patients with better
adherence to therapy
 >80% of total therapy doses
 Black patients have lower
rates of SVR compared to
white (28% vs 52%)
Hepatitis C

47. Direct Acting Antiviral Agents
47
 Standard of care for patients with genotype 1
infection became combination of oral protease
inhibitors with interferon-based therapy
 Direct-acting Antivirals – Protease Inhibitors
 Boceprevir (VictrelisTM)
 4-week lead in period with PegIFN and RBV is required
before adding Boceprevir
 Telaprevir (IncivekTM)
 Telaprevir is given with PegIFN and RBV for 12 weeks,
followed by interferon based therapy alone
Hepatitis C

48. Direct Acting Antiviral Agents
48
 General Principles
 Do not use the protease inhibitors without Ribavirin
 Dose should never be reduced
 Failure to one protease inhibitor is not an indication to switch
 Monitoring
 CBC
 Liver function tests
 Creatinine
 Glucose
 TSH
 Pregnancy
 Depression
Hepatitis C

49. PI Adverse Events
49
Telaprevir Boceprevir
 Rash  Anemia
 Stop if rash is severe,
 Dysgeusia
covering more than 50%
of BSA  Depression
 Pruritis  Neutropenia
 Hemorrhoids  Diarrhea
 Anorectal discomfort
 Insomnia
 Anemia
 Fatigue
 Nausea/Vomiting
Hepatitis C

50. 50
Screening for HCV is recommended for
the following populations:
Screening
* No vaccination is Current or
Recipients of
Persons born previous
available against 1945-1965 injection drug
clotting factors
Hepatitis C before 1987
users
* Screening is
Long-term Persons with
performed with Hemodialysis exposures to
HIV infected
Enzyme persons
patients HCV
immunoassay (EIA)
or Counting Patients with Donors of
Immunoassay Children born to
signs or blood, plasma,
infected
(CIA)for Hepatitis C symptoms of organs, tissues or
mothers
liver disease semen
antibodies
Hepatitis C

51. Questions?
51

52. References
52
 Brundage, Stephanie C and Fitzpatrick, A. Nicole.“Hepatitis A. American Family
Physician, 15 Jun 2006; 73(12): 2162-68.
 Centers for Disease Control and Prevention. Viral Hepatitis Statistics & Surveillance.
Accessed January 2, 2013, at: http://www.cdc.gov/hepatitis/ Statistics/index.htm. Last
Updated June 22, 2012.
 Ghany MG, Strader DB, et al. AASLD Practice Guidelines: Diagnosis, Management, and
Treatment of Hepatitis C: An Update. Hepatology, April 2009;49(4):1335-64.
 Johnston, David E. “Special Considerations in Interpreting Liver Function Tests”. Am Fam
Physician. 1999 Apr 15;59(8):2223-2230.
 Lok, Ana S and McMahon, Brian J. ASSLD Practice Guidelines: Chronic Hepatitis B:
Update 2009. Hepatology, 2009.50(3): 1-34.
 Martin, Annette and Lemon, Stanley. Hepatitis A Virus: From Discovery to Vaccines.
Hepatology, 2006; 43(2): S164-72.
 Yee HS, Chang MF, Pocha C. Update on the Management and Treatment of Hepatitis
Virus Infection: Recommendations from the Department of Veterans Affairs Hepatitis.
Am J Gastroenterol. 24 April 2012. Available online at: www.amjgastro.com