UPDATE on HBV and HCV

1
UPDATE on HBV and HCV

• 2009
• Robert G Gish MD

2
Disclosures relevent to this lecture

• Consultant and speaker
• Schering, Roche, BMS, Gilead, Pharmasset
• Research Grants
• Schering, Roche, BMS, Gilead, Pharmasset
• Investment position
• None

3
Update on HBV and HCV

• Epidemiology
• Screening
• Natural history
• Treatment

4
Chronic Liver Disease Prevalence in United States
Disease Prevalence Rate
Nonalcoholic Fatty Liver Diseasea 17-33
Nonalcoholic Steatohepatitisa 5.7-17
Chronic hepatitis Cb 1.3
Alcoholic liver diseasec 0.8-1.3
Hemochromatosisd 0.5
Chronic Hepatitis Be 0.4
2004 Prevalence
Hepatocellular Cancerf 19,429
a. McCullough AJ. J Clin Gastroenterol
200640S17-S29. b. Armstrong GL et al. Ann
Intern Med. 2006144705-714. c. From
http//www.acg.gi.org/patients/cgp/pdf/alcohol.pdf
. Accessed 04/05/08. d. From http//www.nhlbi.nih.
gov/new/press/01-09-25.htm. Accessed 04/05/08. e.
From http//www.cdc.gov/ncidod/diseases/hepatitis/
resource/PDFs/disease_burden.pdf. Accessed
04/05/08 f. From http//seer.cancer.gov/statfacts/
html/livibd.html. Accessed 04/05/08
5
Who should you testing for viral hepatitis?

• Patients typically enter this diagnostic group
  with
• a history of
• Elevated liver tests
• or
• Risk history
• Also few symptoms are specific for liver disease
  and thus an evaluation should take place if
• signs of liver failure

6
Liver Tests

• Liver Enzymes
• AST
• ALT
• Alkaline Phosphatase
• GGT
• Liver Synthetic Tests
• Bilirubin
• Albumin
• Protime/INR

True liver function tests
7
Elevated Liver TestsDifferential Diagnosis

• Population based survey in US 1999-2002 estimated
  abnormal ALT (gt45 IU/mL) in 8.9 of population
• Symptomatic vs Asymptomatic?
• Acute vs Chronic?
• Hepatitic vs Cholestatic?

8
Evaluation of Liver Enzymes

• First step is to repeat the test!!
• Many many things can cause a one-time elevation
  of liver tests
• A mild elevations (lt2x Healthy) should be
  monitored (2-3x) for at least 6 months before a
  full serologic work-up is done
• After intervention stop alcohol (example)
• Exception is suspected viral hepatitis
• Order serologies in high risk people
• Abnormal Liver Function
• Immediate evaluation !!!

9
6 key tests for increased liver enzymes

• Alcohol history
• CAGE, MAST
• HCV antibody
• HBsAg
• Iron Sat
• Medication and herbal, OTC history
• metabolic syndrome tests
• BMI
• HTN
• Lipids
• Glc fasting
• Waist circumference

10
Differential Diagnosis

• Hepatitic
• Viral Hepatitis A, B, C, D, E
• Alcoholic and Nonalcoholic Steatohepatitis
• Autoimmune
• Hemochromatosis
• Wilsons disease
• Alpha-1 antitrypsin

• Cholestatic
• Obstruction
• Gallstones, malignancy, parasites
• Primary Biliary Cirrhosis
• Primary Sclerosing Cholangitis
• Infiltrative diseases metastatic cancer,
  sarcoidosis, amyloidosis
• Medications

• Other
• Drugs
• Thyroid disorders
• Celiac disease
• Vascular disease CHF, Budd Chiari syndrome,
  Sinusoidal obstructive syndrome

11
ALT Value According to Sex and BMIAfter Modeling
by Neural Network
ALT (IU/L)
45.56
RBF2
11.53
1.00
Sex
0.00
36.00
BMI
16.00
Piton A, et al. Hepatology. 1998271213.
12
Healthy ALT

• lt19 for women
• lt25-30 for men

13
Normal Aminotransferase Levels and Risk of
Mortality from Liver Diseases

• Study design Prospective cohort study Korean
  Medical Insurance Corporation 8-year follow-up
  94,533 men and 47,522 women aged 35 to 59
• Results ...findings indicate that serum
  aminotransferase concentration is associated with
  mortality from liver disease, even within the
  current normal range best cut-off value by ROC
  of ALT for prediction of liver diease in men was
  30 U/L
• Conclusions People with slightly elevated
  aminotransferase activity, but still within the
  normal range, should be closely observed and
  further investigated for liver disease

Kim HC, et al. BMJ 2004328983.
14
Normal Aminotransferase Levels and Risk of
Mortality from Liver DiseasesProspective Cohort
Study
ALT (IU/L) No (men) RR (95 CI) lt 20
37425 1.0 (0.7-1.4) 20-29
36589 2.9 (2.4-3.5) 30-39 11975
9.5 (7.9-11.5) 40-49 4068 19.2
(15.3-24.2) 50-99 3887 30.0
(25.0-36.1) ? 100 589 59.0
(43.4-80.1)
"Normal
"Elevated
Kim HC, et al. BMJ 2004328983.
15
Normal Serum AST and ALT and Risk of Mortality
from Liver Diseases Prospective Cohort Study

• DESIGN
• Prospective, cohort study
• Cause of death from death certificates
• 94,533 males and 47,522 females ages 35-59 with 8
  years follow-up
• Number with CHB unknown
• OBJECTIVE
• Determine liver mortality in individuals with
  normal ALT (lt40 IU/L)
• OUTCOMES
• 690 deaths from liver disease (LD)
• Death from LD associated with baseline age, AST,
  BP, FHx of LD, elevated glucose or cholesterol
• ALT gt20 increased risk for death from LD

Risk of death from liver disease based on ALT and
AST
RR of Death from LD RR of Death from LD
AST Male Female
lt20 1 1
20-29 2.5 3.3
30-39 8 18.2

ALT
lt20 1 1
20-29 2.9 3.8
30-39 9.5 6.6
Kim HC, et al. BMJ 2004328983.
16
Hepatitis B

• 2 Billion exposed
• 400 million infected worldwide
• 2 million infected in the US
• Death rate due to cirrhosis or liver cancer
• 25-30 in patients with vertically acquired HBV
• 7 in patients with adult acquired HBV

17
Concept

• HBV is not curable
• HBV is suppressible and controllable

18
HBV Phase I

• HBsAg Infection
• Anti-HBs Immunity
• Anti-HBc Exposure

19
HBV Phase II

• If a patient is HBsAg positive
• Order
• HBV DNA quant
• HBeAg
• Anti HBe
• Also
• HDV
• Antigen
• Antibody

20
HBV Phase III

• If a patient is HBsAg positive
• Order
• Anti HAV
• Vaccinate if not immune
• Also
• HCV
• HIV
• No make sure patient is not coInfected

21
HBV Serologies
HBsAg HBsAb HBcAb HBV DNA Interpretation
- IgM
IgG
- - -
- -
- - -
Acute infection
Chronic infection
Immunized
Past Exposure/with Immunity/Clearance
False pos or Past Exp
22
HBV DNA Quantification

• Levels of HBV DNA important
• To decide if patients liver disease is active or
  inactive
• To define a patients long term risk of HCC and
  cirrhosis
• To allocate patient to proper treatment and or
  monitoring status

23
HBV Serologies Interpretation when HBV DNA
positive

• HBeAg only applicable in patients who are
  chronically infected or carriers
• Wild type (or mixed infections wild type and
  precore and/or core promoter variants)
• Negative precore/core promoter mutant variant of
  virus, still can be infective, still has
  advancing disease
• Positive increased infectivity
• When to consider stopping treatment if treatment
  is initiated

24
Role of Liver Biopsy in Patients With Normal ALT
and High Viral Load
HBV
Stage of Fibrosis by ALT Group
70
Stage 0
60
Stage 1
50
Stage 2
Stage 3
40
Patients,
Stage 4
30
24
20
10
0
PNALT (n 57)
ALT 1-1.5 ULN (n 23)
ALT gt 1.5 ULN (n 110)
Lai et al. AASLD 2005. Abstract 67571.
25
Rationale for Screening for HBV

• As many as 25 of children infected in their
  first year of life will eventually die from
  HBV-related complications, 7 of adult aquired
  disease will die of complications of cancer or
  cirrhosis
• Less than 5 of adults acquiring acute infection
  develop chronic infection
• Among children infected with HBV, 90 become
  chronic carriers, although they rarely develop
  acute illness
• Vast majority of individuals with chronic HBV
  are asymptomatic

Centers for Disease Control and Prevention. MMWR
Morb Mortal Wkly Rep. 200857 (No. RR-8)10 (A).
26
Who Should Be Screened?Adult Indications for HBV
Screening and/or Vaccination
Demographic Persons born in regions of high and intermediate HBV endemicity (HBsAg prevalence gt2) US-born individuals not vaccinated as infants whose parents were born in regions with high HBV endemicity (gt8)
Behavioral Injection-drug users men who have sex with men
Occupational Persons who are the source of blood or body fluid exposures that might warrant postexposure prophylaxis (eg, needlestick injury to a health care worker or sexual assault)
Centers for Disease Control and Prevention. MMWR
Morb Mortal Wkly Rep. 200857 (No. RR-8)10 (A).
27
Who Should Be Screened?Adult Indications for HBV
Screening and/or Vaccination (contd)
Other contacts Household contacts, sex partners of persons with chronic HBV
Medical Persons needing immunosuppressive therapy, including chemotherapy, immunosuppression related to organ transplantation, and immunosuppression for rheumatologic or gastroenterologic disorders persons with elevated ALT/AST of unknown etiology donors of blood, plasma, organs, tissues, or semen persons infected with human immunodeficiency virus hemodialysis patients all pregnant women infants born to HBsAg-positive mothers
ALT/ASTalanine transaminase/aspartate
transaminase. Centers for Disease Control and
Prevention. MMWR Morb Mortal Wkly Rep. 200857
(No. RR-8)10 (A).
28
Geographic Regions With HBV Surface Antigen
(HBsAg) Prevalence of ?2
Regiona HBsAg Prevalence ?2b
Africa All countries
Asiac All countries
Australia and South Pacific All countries except Australia and New Zealand
Middle East All countries except Cyprus and Israel
Eastern Europe All countries except Hungary
Western Europe Malta, Spain, and indigenous populations in Greenland
North America Alaska natives and indigenous populations in Northern Canada
Mexico and Central America Guatemala and Honduras
South America Ecuador, Guyana, Suriname, Venezuela, and Amazonian areas of Bolivia, Brazil, Colombia, and Peru
Caribbean Antigua-Barbuda, Dominica, Grenada, Haiti, Jamaica, St. Kitts-Nevis, St. Lucia, and Turks and Caicos Islands
aA complete list of countries in each region is
available at http//www.cdc.gov/travel/destination
List.htm bestimates of prevalence of HBsAg, a
marker of chronic HBV infection, are based on
limited data and might not reflect current
prevalence in countries that have implemented
childhood HBV vaccination. In addition, HBsAg
prevalence might vary within countries by
subpopulation and locality cAsia includes 3
regions Southeast Asia, East Asia, and Northern
Asia. Centers for Disease Control and Prevention.
MMWR Morb Mortal Wkly Rep. 200857 (No. RR-8)10
(A).
29
Screening Programs

• San Francisco HBV-free
• A major collaborative involving city government,
  private health care and nonprofit community
  organizationsincluding California Pacific
  Medical Center and AsianWeek Foundation
• Two-year campaign to screen all Asian and Pacific
  Islander residents for HBV infection
• The largest health care campaign to target Asians
  and Pacific Islanders in the United States

Hep B Free. http//www.sfhepbfree.org/news_042407.
htm. Accessed September 25, 2008.
30
Treating HBV

• Treatable but not curable

31
Key Take Home Point

• HBV DNA quantification
• Correlates with risk of cancer and cirrhosis
• Independent of ALT or HBeAg status

32
HBV Risk (HCC and Cirrhosis) Score
high risk low risk
Gender
Age
HBV DNA
ALT
Fibrosis
Cirrhosis
Genotype
CP and PC mutations
Coinfection
family history HCC
33
Approved Therapeutic Options in the United States

• First line
• Entecavir (Baraclude)
• Tenofovir (Viread)
• Pegylated interferon (Pegasys)
• Second line
• Adefovir dipivoxil (Hepsera)
• Telbivudine (Tyzeka, Sebivo)
• Third line
• Lamivudine (Epivir-HBV, Zeffix, or Heptodin)
• Rarely used
• Interferon alpha (Intron A)

Lok et al. Hepatol. 200745507-539 (A). EASL
Guidleines 2009, NIH Consensus Conf 2008
34
Clinical Considerations for Treatment

• Which criteria should be used to start, continue,
  switch, or stop therapy?
• How long should therapy last?
• How to prevent resistance?
• Which agent to use?
• Use of combination therapy
• Is combination of agents more effective?
• When should combination therapy be used as
  initial therapy?

35
Who Needs Treatment?

• Main parameters to determine indication
• HBeAg and anti-HBe status
• HBV DNA quantification
• Liver enzymes (ALT, AST)
• Liver biopsy
• Assess fibrosis
• Exclude concomitant liver disease (eg, fatty
  liver)

Lok et al. Hepatol. 200745507-539 (A).
36
Management of Chronic HBV Infection
 HBV DNA Level ALT Activity ALT Activity
 HBV DNA Level 17-25 ? U/L gt 17-25 ? U/L
lt 104 copies/mL lt 2000 IU/mL Observe? Perform biopsy
gt 104 copies/mL gt 2000 IU/mL Perform biopsy and treat if active HBV infection Treat HBeAg() ? 6 m after eAg seroconversion HBeAg(-) Prolonged treatment (? 24 months) beyond NAT? negative (Consider biopsy or use noninvasive fibrosis testing)
? ULN for a person with a normal BMI ?Treat any
patient with cirrhosis who is NAT positive, refer
to specialist
Refer patients with cirrhosis, resistance, liver
cancer
Rule out fatty liver and other causes of CLD
Consider 3-5 years
NAT, nucleic acid testing, such as PCR, bDNA or
TMA
As modified from Gish. Clin Liver Dis.
20059(4)541-565.
37
Goals of Therapy

• The overall goal of treatment in all HBV patients
  is
• Suppression of HBV DNA levels to undetectable
  amounts to decrease progression to cirrhosis,
  HCC, and liver-related mortality
• HBsAg seroconversion
• Normalization of serum liver enzymes
• Improvement of liver histology
• Goals of therapy in HBeAg-positive patients
• HBeAg seroconversion
• Goals of therapy in HBeAg-negative patients
• No clear end point of therapy
• Relapse is common even when treatment is
  discontinued after 2 to 3 years of successful
  therapy
• Resistance to antiviral agents is the primary
  consideration in choosing first-line therapy
  given the need for long-term treatment

Modified from Lok et al. Hepatol. 200745507-539
(A).
38
Summary Recommendations

• HBV DNA positive Treat
• Efficacy, safety and resistance profile
• First Line Therapy 90 are HBV DNA negative at
  2-5 years
• Entecavir
• Tenofovir
• Second Line Therapy special cases
• Adefovir (availability)
• Telbivudine (preganancy, HIV co infection without
  ART therapy)
• Third Line Therapy pregnancy or very short term
  use is role
• Lamivudine
• Pursue HBsAg seroconversion

39
Resistance is associated with

• Treatment failures with
• Liver disease flares
• Liver decompensation
• Death
• Urgent liver transplant
• HBV vaccine failure

40
Resistance Rates
Lamivudine Adefovir Entecavir Tenofovir
n 998 125 108 375
Time 5 years 5 years 6 years 2 years
Rate of resistance 63 29 to 42 1.2 Rx naïve 50 if preexisting 204/180 mutations 0
Lok et al. Gastroenterology. 20031251714-1722
(B) Hadziyannis et al. Gastroenterology.
20061311743-1751 (A) Herpcera (adefovir
dipivoxil) prescribing information. Gilead
Sciences, Inc. 2008 (A) Presented at 18th
Conference of the APASL March 23-26, 2008
Seoul, Korea (Bi).
41
Definitions Antiviral Resistance

• Genotypic resistance
• Presence of mutations associated with decreased
  susceptibility to antiviral agents
• Phenotypic resistance
• In vitro demonstration of decreased
  susceptibility (EC50)
• Virologic breakthrough
• Increase in viral levels ( secondary Tx failure)
• Biochemical breakthrough
• Increase in ALT

Lok et al. Hepatol. 200745507-539 (A).
42
Summary

• HBV is a serious US and Global health problem
• Screen appropriate patients
• Vaccinate patients at risk for infection
• Treat patients at risk of progression
• Although not curable, disease is suppressable
  with improved patient outcomes

43
HCV The Facts

• Estimated 170,000,000 infected people worldwide
  ( 3 of world population)
• Risk of chronicity 55 85
• Risk of cirrhosis 20 within 20 years
• 30 within 30 years
• Cirrhosis-related mortality 2 5 / year
• Incidence of liver cancer 3 10 / year among
  patients with cirrhosis
• HCV is curable

44
Estimated HCV Prevalence in Select
PopulationsUnited States
Incarcerated, 310,000 (15)1Ever incarcerated,
1,400,000
Injection drug users300,000 (80-90)2,3
HIV-infected 300,000 (30)4
Alcoholics240,000 (11-36)5
Living below poverty level 940,000 (2.4)6
Homeless 175,000 (22)7
Veterans 280,000 (8)8
Children (6-19 years) 100,000 (0.1)9
1MMWR Recomm Rep. 200352(RR-1)1-36. 2Edlin.
Hepatology. 200236(5 Suppl 1)210-9. 3NHSDA
Report. 2003. 4Khalili and Behm. Clin Inf Dis.
200031154-61. 5Labreque and Sandt. In Hepatitic
C Choices. 2002. 6Alter et al. N Engl J Med.
1999341(8)556-562. 7Nyamathi et al. J Gen
Intern Med. 200217(2)134-43. 8Bräu et al. Am J
Gastroenterol. 200297(8)2071-8. 9Jonas.
Hepatology. 200236(5 Suppl 1)S173-8.
45
Rules for HCV

• All patients with HCV Aby need quantitative RNA
  test assessment
• 20 will develop cirrhosis if HCV RNA positive
  and elevated liver enzymes above healthy range
• increased risk of cirrhosis
• if HIV, Alc abuse, organ transplant, fatty
  liver
• 20 risk of HCC if cirrhosis is present
• All patients who are RNA positive should
  presented with the option of a liver biopsy
• 3 transmission vertical, needlestick, sexual
  transmission

46
Predicted Future HCV Costs
Year
47
Predicted Future HCV Mortality
Year
48
Spectrum of HCV infection
0
Acute HCV Infection
15-30
55-85
Recovery
Chronic HCV Infection
30
Chronic Hepatitis C
Normal ALT
Mild
Moderate
Severe
Cirrhosis 20
Hepatocellular Carcinoma
End-Stage Liver Disease
Liver Transplantation
Death
49
Number of Patients on the Waiting List Active at
Year End, 1995-2004
16, 000
14, 000
12, 000
10,000
Number of Patients on Waiting List
8,000
6,000
4,000
2,000
0
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004 -Current
Year
Source 2005 OPTN/SRTR Annual Report, Table 9.1a
50
Natural History of HCV Cirrhosis
Clinical complications thatled to
decompensation(N355)
Appearance of HCC(N384)

Fattovich G et al. Gastroenterology.
1997112466.
51
Natural History of HCV Cirrhosis
100 80 60 40 20 0
1
2
3
4
5
6
7
8
9
10
0
Adapted from Fattovich G et al. Gastroenterology.
1997112466-467 and Forman LM et al.
Gastroenterology 2002122889-896 .
52
The Evolution of HCV TherapyThe Goal is
Virologic Cure
1986
1998
2001
2002
54-56
SVR ()
42
39
34
16
6
PEG-IFN /RBV 12m
IFN/RBV 12m
IFN 6m
IFN/RBV 6m
IFN 12m
PEG-IFN 12m
Strader DB, et al. Diagnosis, Management, and
Treatment of Hepatitis C. Hepatology
2004391147-1171.
53
Predicting SVR in Patients Treated with PEG-IFN
?-2a (40KD)/RBV
Virologic Response ()
HCA RNA Status HCA RNA Status HCA RNA Status HCA RNA Status HCA RNA Status HCA RNA Status HCA RNA Status
Week 4 Negative gt2 Log10 lt2 Log10 gt2 Log10 lt2 Log10 Any
Week 12 Negative Negative Negative gt2 Log10 gt2 Log10 Positive
Week 24 Negative Negative Negative Negative Negative Positive
Ferenci P, et al. J Hepatol. 200543(3)425-433.
54
Other Predictors of HCV Treatment Outcomes

• HCV Genotype
• G 1 and 4
• 48 weeks treatment
• Cure rates
• HCV G1 40-50
• HCV G4 50-60
• G 2
• 12-24 weeks
• Cure rates 80-90
• G 3
• 24-?48 weeks
• Cure Rates 70-80

55
Do we change outcomes by treatment ?

• Unqualified yes
• Decrease
• Liver failure
• Liver transplant
• Liver cancer
• Infectivity
• Improve
• QOL

56
Emerging HCV Therapies
Specifically Targeted Antiviral Therapy for HCV
(STAT-C)
Enzyme Inhibitors
Genome Sequence-Based
Other

• IFN and RBV modifications
• albumin IFN, omega IFN
• Taribavirin (viramidine)

Polymerase
RNA interference (substantial challenges)
Antisense Oligonucleotides (halted)
Protease

• Immune approaches
• Therapeutic vaccines
• Toll-like receptor agonists
• Yeast expressing HCV Ag

• Targeting cellular factors
• Cyclophilin antagonists
• Nitazoxanide
• Celgosovir

Ribozymes (halted)
Helicase (no trials yet)
57
The Promise of Combination TherapyIn Vitro
Combinations Studied
Drug 1 Drug 2 Enhanced Suppression Resistance Studies Resistance Studies
Drug 1 Drug 2 Enhanced Suppression Decreased Emergence of de Novo Resistance Suppression of Preexisting Resistant Variants
Boceprevir1 Valopicitabine Yes Yes Yes
Boceprevir2 HCV-796 Yes Yes Yes
ITMN-1913 R1479 Yes NA Yes
NM1074 ACH-806 Yes NA NA
Telaprevir4 ACH-806 Yes NA NA
Telaprevir5 R1479 NA Yes NA
Valopicitabine6 Various NA NA Yes
NAnot applicable
1. Ralston. J. Hepatol. 200746S298. 2. Howe. J.
Hepatol. 200746S165. 3. Seiwert. J. Hepatol.
200746S167. 4. Huang. J. Hepatol. 200746S8.
5. McCowen. 14th International Symposium on
Hepatitis C Virus and Related Viruses. September
9-13, 2007. Abstract P-265. 6. Bichko. J.
Hepatol. 200746S163.
Slide by Ira M. Jacobson, MD
58
3-Drug Synergistic Interactions of STAT-C Agents
In Vitro

• Nonnucleoside
• GSK NNI
• Wyeth NNI

• Nucleoside
• 2-C-methyladenosine
• GSK PI

• Protease inhibitor
• Vertex PI
• BILN 2061

• All 3-way combinations demonstrated synergy
• No data on resistance shown
• Additional study of ACH-806 (NS4A antagonist)
  PI, NN, or NUC showed synergy
• (Wyles. AAM 2008521862)

Grunberger. JID 200819742
59
HCV Summary

• Is a worldwide health problem
• Patients with elevated liver tests or risk
  factors need to be screened for HCV and
  subsequently HCV RNA testing
• Patients with HCV infection defined by antibody
  positive and RNA positive need to be seen by a
  specialist for discussions about liver biopsy and
  treatment as well as assessment for cirrhosis
• HCV is curable
• We change HCV outcomes by treatment and cure