Viral Hepatitis Medicine Student Lecture

1
Viral HepatitisMedicine Student Lecture

• David R Nelson, M.D.
• Professor of Medicine
• Director, Hepatology and Liver Transplantation
• University of Florida

2
Case 1

• 29 y/o female came to your clinic with
• Jaundice, Abdominal pain, Nausea / Vomiting
• AST-2,000 ALT- 2,500, Total bili 1.8
• She denies IVDA or any recent drug/medicine
  exposure, but had unprotected sex about 6 weeks
  ago
• Ultrasound shows normal appearing liver and blood
  flow
• Her diagnosis is

3
Causes of Acute Hepatitis
4
Case

• 38 y/o male with past medical history of abnormal
  ALT for past 4 years. He had a blood tx as a
  child due to MVA. Patient came to your clinic
  with
• ALT 150, AST 100
• HBsAb , HBcAb
• HCV Ab
• HAV IgG
• What is your dx?

5
Causes of Chronic Hepatitis
Abbreviations NAFLD nonalcoholic fatty liver
disease AIH autoimmune hepatitis PBC primary
biliary cirrhosis PSC primary sclerosing
cholangitis, A1AT alpha-1 antitrypsin
deficiency, HHChereditary hemochromotosis
6
Acute Viral Hepatitis by Type, USA 1982-1993
34
47
16
Hepatitis A
3
Hepatitis B
Hepatitis C
Hepatitis Non-ABC
Source CDC Sentinel Counties Study on Viral
Hepatitis
7
Hepatitis A Virus
Nucleic Acid 7.5 kb ssRNA
8
(No Transcript)
9

10
Hepatitis A Prevention - Immune Globulin

• Preexposure
• Travelers to high HAV-prevalence regions
• Postexposure (within 14 days)
• Routine
• Household and other intimate contacts
• Selected situations
• Institutions (e.g. daycare centers)
• Common source exposure (e.g. food prepared by
  infected food handler)

11
Hepatitis A Pre-exposure Vaccination

• Persons at increased risk or danger of infection
• Travelers to intermediate and high HAV
  prevalence areas
• Men having sex with men
• Injecting drug users
• Persons with chronic liver disease
• Communities with high rates of hepatitis A(e.g.,
  Alaskan Natives, Native-Americans)
• Routine pre-school childhood vaccination

ACIP Recommendations MMWR 1999 48(RR12)1
12
Hepatitis E Virus
Nucleic Acid 7.5 kb ssRNA
13
Clinical Characteristics
Hepatitis E
14
Hepatitis B Virus

• Hepadnaviridae member that primarily infects
  liver cells
• 50 to 100 times more infective than HIV
• Multiple genotypes exist (A-H)
• DNA virus found in blood and body fluids
• Able to survive in dried blood for longer than 1
  week

15
gt 350 million carriers (HBsAg gt 6 months)
Geographic Distribution of Chronic HBV Infection
10th cause of death (1 million / year) Cirrhosis
in 20 (75 - 100 million) HCC in 5 - 10 (20 -
40 million)
HBsAg Prevalence
?8 - High
2-7 - Intermediate
lt2 - Low
16
HBV Sources of Infection
Household, 3
MSM, 23
Other, 23
Sex contact, 23
IDU, 20
Multiple sex partners, 24
Many patients do not reveal IDU as source of
infection
Centers for Disease Control and Prevention.
Hepatitis B. In Atkinson W et al, eds.
Epidemiology Prevention of Vaccine-Preventable
Diseases. 8th ed Washington DC Public Health
Foundation 2005191-212.
17
Signs and Symptoms of Acute Hepatitis B

• About 30 of persons have no signs or symptoms
• If symptoms are present, generally nonspecific
  including

18
Progression to Chronic Hepatitis B Virus Infection
Typical Serologic Course
Acute (6 months)
Chronic (Years)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titer
HBV DNA
IgM anti-HBc
Years
0
4
8
12
16
20
24
28
32
36
52
Weeks after Exposure
19
Interpretation of Serologic Markers
20
Hepatitis B Disease Progression
Liver Cancer (HCC)
5-10 1
2-6
Acute Infection
Death
Liver Transplantation
Chronic Infection
Cirrhosis
10-30 1
90 in perinatal 30-90 in childrenlt5yrs old 5
in healthy adults Higher in HIV, immune suppressed
Chronic HBV is the 6th leading cause of liver
transplantation in the US4
Liver Failure (Decompensation)
23 within 5 years
1. Torresi J et al. Gastroenterology. 2000. 2.
Fattovich G et al. Hepatology. 1995. 3. Moyer LA
et al. Am J Prev Med. 1994. 4. Perrillo R et al.
Hepatology. 2001.
21
The REVEAL Study Regression Analysis of Serum
Level of HBV DNA and Risk of Cirrhosis
Multivariate-adjusted Relative Risk
?1 million
100,000-999,999
10,000- 99,999
300- 9,999
lt300
HBV DNA, copies/mL
Iloeje UH et al. Gastroenterology 2006
130678-86.
22
The REVEAL StudyRegression Analysis of Serum
Level of HBV DNA and Risk of HCC
Multivariable-Adjusted HR
?1 million
100,000-999,999
10,000- 99,999
300- 9,999
lt300
HBV DNA, copies/mL
Chen C-J et al. JAMA 200629565-73.
23
Targeted Surveillance for HCC
Non-hepatitis B Cirrhosis
Hepatitis B Carriers

• Hepatitis C
• Alcoholic cirrhosis
• Genetic hemochromatosis
• Primary biliary cirrhosis
• Other (? efficacy)
• A1AT deficiency
• NAFLD
• Autoimmune hepatitis

• Asian males gt age 40
• Asian females gt age 50
• All cirrhotic HBV carriers
• Family history of HCC
• Africans gt age 20
• High HBV DNA

• Surveillance for HCC should be with ultrasound
  at
• 6 to 12 month intervals AFP is not adequate

Bruix J and Sherman M. Hepatology 2005421208
24
Prevention of Transmission of Hepatitis B
Vaccination

• Vaccinate Sexual and household contacts
• Newborns of HBV-infected mothers
• HBIG and
• hepatitis B vaccine at delivery
• 3. Test for response to vaccination
• infants of HBsAg-positive mothers (9 to 15
  months )
• health care workers,
• dialysis patients, and
• sexual partners
• 4. Follow-up testing of vaccine responders
• Annually for chronic hemodialysis patients

1-2 months
25
Goals of Treatment in HBV

• Reduce the risk of disease progression
• Reduce the risk of hepatocellular carcinoma
• Loss of HBeAg, HBeAg ? HBeAb
• Undetectable HBV-DNA
• Normalization of ALT
• Histologic Response
• HBsAg ? HBsAb

Virologic Response
26
Treatment Criteria for Chronic Hepatitis B
aDegertekin B, Lok ASF. Hepatology
200949(S5)S129-S137. bEuropean Association for
the Study of the Liver J Hepatol
200950227-242. cKeeffe, EB et al. Clin
Gastroenterol Hepatol 200861315-1341. dYiaw
Y-F et al. Hepatol Int 20082263-283. eLok ASF,
McMahon BJ. Hepatology 2007 45507-539.
27
Undetectable HBV DNA in HBeAg-Negative Patients
at 1 Year
Collation of currently available data Not from
head-to-head studies using different DNA assays
undetectable HBV DNA 300400 cp/mL
Marcellin, AASLD 2007 Lai et al., N Engl J Med.
2006 Lai et al., N Engl J Med. 2007
28
Undetectable HBV DNA in HBeAg-Positive Patients
at 1 Year
Collation of currently available data Not from
head-to-head studies using different DNA assays
undetectable HBV DNA 300400 copies/mL
Heathcote, AASLD 2007 Chang, NEJM 2006 Lai CL
NEJM 2007 Lau, NEJM 2005
29
Cumulative Incidence of HBV Resistance
Lamivudine
Entecavir
100
100
HBeAg() and (-) patients
HBeAg() patients
80
80
67
57
60
60
Cumulative probability of resistance ()
Incidence ofresistance ()
40
40
40
17
20
20
0.2
0.5
1.2
1.2
1.2
ND
0
0
663
278
149
120
108
N
58
58
58
58
N
1
2
3
4
5
1
2
3
4
5
Year of treatment
Year of treatment
100
100
Adefovir
Telbivudine
80
80
HBeAg(-) patients
HBeAg()
HBeAg(-)
60
Cumulative probability of resistance ()
60
Cumulative incidence of resistance ()
40
40
29
22
18
20
11
20
9
4
3
3
0
ND
ND
ND
0
0
183
134
NA
NA
60
N
458
222
458
222
N
1
2
3
4
5
1
2
3
4
5
Year of treatment
Year of treatment
30
Resistance Profile First Line Treatment Options
Have The Lowest Resistance Rates
Highest Rate of Resistance
Lowest Rate of Resistance
Lamivudine 65 to 70 at 4 to 5 years
Adefovir dipivoxil 29 at 5 years
Tenofovir DF in treatment naïve patients (0 at
2 years)
Entecavir in the absence of prior lamivudine
resistance (1.25 at 5 years)
Telbivudine 25 in HBeAg-positive patients 11
in HBeAg-negative patients at 2 years
Patients with LAM resistance have a 51 rate of
novel mutations after 5 years of entecavir
therapy Keeffe, E, et al. Clinical
Gastroenterology and Hepatology 2008doi
10.1016/j.cgh.2008.08.021 (e-pub).
31
Hepatitis D Virus Morphology and Characteristics
32
Modes of HDV infection
33
HCV Life-Cycle
Immune Recognition
Immune Response
Cell Binding and Infection
CD4 CD8 NK DC
Replication
Effector
HCV
Cytokines
HSC
Viral Packaging and Release
Fibrosis
34
The Burden of Liver Disease Associated with HCV
is Increasing

• An estimated 5 million Americans have been
  infected with HCV, of whom 4 million are
  chronically infected
• Approximately 30,000 people in the US are
  infected with hepatitis C each year
• Hepatitis C is the leading causes of liver
  disease and cirrhosis in US
• 15,000- 20,000 people die of hepatitis C each
  year in the US
• The CDC estimate that the number of annual
  deaths from hepatitis C will triple in the next
  10 - 20 years
• The estimated medical and work loss costs per
  year of hepatitis C is over 800 million

Source American Liver Foundation
35
Course of Acute HCV Infection
HCV RNA positive
1000
Anti-HCV
800
Symptoms
600
ALT (IU/L)
400
200
Normal ALT
0
0
2
4
6
8
10
12
24
1
2
3
4
5
6
7
Weeks
Months
Time After Exposure
Hoofnagle JH. Hepatology. 19972615S. Carithers
RL Jr, et al. Semin Liver Dis. 200020159-171.
Pawlosky JM. Hepatology. 200236(suppl
1)S65-S73. NIH Management of Hepatitis C
Consensus Conference Statement. June 10-12, 2002.
Available at http//consensus.nih.gov/2002/2002He
patitisC2002116html. Accessed April 10, 2007.
36
Symptoms, or Lack of, in Chronic HCV Infection
Symptomatic37
100
Cirrhosis7
80
80
60
Patients ()
40
20
0
Fatigue
56Asymptomatic
37
ALT Elevations Are Not Indicative of Chronic HCV
Infection
100
80
60
Patients With HCV infection ()
43
42
40
15
20
0
PersistentlyNormal ALT
IntermittentlyElevated ALT
Persistently Elevated ALT
Inglesby TV, et al. Hepatology. 199929590-596.
38
Prevalence of HCV Dependant on Risk Factors

• Hemophilia 74-90
• IVDA 72-89
• Prison 40
• HIV 30-40
• Blood transfusion prior to 90 5-9
• Infants to HCV Mothers 5
• Sexual Partner 0.5-3
• General Population 1.8

Adapted from MMWR.1998475.
39
Aging of the Population With HCV
Source Armstrong, G. L. et. al. Ann Intern Med
2006144705-714
40
HCV Disease Progression
Time 20-30 years
HCV infection
60-851
Chronic HCV
Cirrhosis
Hepatic Failure
203
20-502
204
Liver Transplant Candidates
Liver Cancer
1. NIH Consensus Development Conference
Statement March 24-26, 1997. 2. Davis GL et al.
Gastroenterol Clin North Am. 199423603-613. 3.
Koretz RL et al. Ann Intern Med.
1993119110-115. 4. Takahashi M et al. Am J
Gastroenterol. 199388240-243.
41
Histologic Progression of HCV Monitored by Liver
Biopsy

• Inflammation Grade
• Measure of severity and ongoing disease activity
• 0-4 (METAVIR)
• Inflammation leads to scarring/fibrosis
• Fibrosis Stage
• Amount of fibrous scar tissue
• 0-4 (METAVIR)
• Stage 4 cirrhosis
• Indicates long-term disease progression

No fibrosis
Cirrhosis
Brunt EM. Hepatology. 200031241-246.
42
Natural History of Compensated HCV Cirrhosis A 17
Year Cohort Study(n214)
Complication Death HCC Ascites Jaundice GI
Bleed PSE
Total 35 32 23 17 6 1
Annual 4.0 3.9 2.9 2.0 0.7 0.1
HCC was the main cause of death (44) and the
first complication to develop (21)
Sangiovanni A, et al Hepatology 2006431303
43
Liver Cancer Has the Fastest Growing Death Rate
in the US
Trends in US Cancer Mortality Rates
All Cancers (Average)
Testis
Esophagus
Lung and Bronchus (Females)
Thyroid
Uterus
Liver
Annual Percent Change (1994-2003)
Represents the annual percent change over the
time interval National Cancer Institute Website.
Available at http//seer.cancer.gov/csr/1975_200
3/sections.html.
44
Improvements in Therapy of HCV
1991
1998
2001
2002
Sustained Virologic Response ()
IFN 6m
IFN/RBV 6m
Peg-IFN/ RBV 12m
IFN 12m
IFN/RBV 12m
Peg-IFN 12m
Strader DB et al. Hepatology 2004391147-1171
45
Treatment regimen PEG-IFN exposure Ribavirin
exposure
Host factors Age, gender, race obesity, IR,
ETOH Genetic factors
Response factors IFN/RBV
Disease features Fibrosis, steatosis,
co-infection (HBV, HIV)
Viral factors Genotype Viral load
46
Genetic Variation in IL28B predicts HCV Viral
Clearance
DL Ge et al. Nature 000, 1-3 (2009)
doi10.1038/nature08309
47
Algorithm for HCV Therapy
Patients infected with HCV genotype 1 treated
with Peg- IFN plus ribavirin
RVR
No RVR
Week 4
Consider treating select patients (low baseline
HCV RNA) for a total of 24 weeks. Treat all
others for 48 weeks
Complete EVR
Non-EVR
Partial EVR
Week 12
Consider treating patients for a total of 72 weeks
Low probability of SVR. Alternative strategies
are required
Treat patients for a total of 48 weeks
Marcellin P, et al. Presented at AASLD 2007. Nov.
2-6, 2007. Boston, MA. Abstract 1308.
48
Summary

• Viral hepatitis is a common cause of acute and
  chronic liver disease
• Diagnosis relies on clinical suspicion and
  serology/virology for confirmation
• HBV is a treatable and preventable disease
• HCV can be cured with adequate therapy