Viral Hepatitis

1. Update on
Viral Hepatitis
Geri Brown, M.D.
Department of Internal Medicine
March 19, 2015

2. Case study
 71 yo white male with 2 wk hx of jaundice, dark
urine, N/V, ate at new restaurant
 Social: Retired
 Physical Exam: 6 ft, 180 lbs, jaundice, no
evidence of chronic liver disease
 Laboratory tests: AST 1584, ALT 1623, AP 321,
TB 25, WBC 10.6, Platelets 160K, INR 1.4
 U/S Mild increased echogenicity, nl CBD
 Serology: HAV IgM - Reactive

3. HEPATITIS A VIRUS
RNA Picornavirus
-Single serotype worldwide
Acute disease
-Asymptomatic or symptomatic
Transmission
-Food / Water Borne
-Nosocomial
Serology
-HAV IgM-acute
-HAV (total)-immune

4. Diagnosis and Management
 Diagnosis and Management of Acute Hepatitis A
– History
– Aminotransferases – Hepatocellular Injury
– HAV IgM
– Supportive care (Liver transplantation in FHF)
 Mortality
– Case fatality rates - 0.004% - 5-14 years
– .03-.06 % - 25-35 years
– 3-6% >55 years
 Prevention of Hepatitis A
– Vaccination (HAVRIX, 0 and 6-12 mos)
– Proper hygiene
 Vaccine recommendations
– All children starting at age 1 year
– Travelers to certain countries
– Others at risk
• Persons with chronic liver disease

5. Case study 2
 26 year old African American male with loss of appetite,
N/V, yellow eyes, dark urine
 Social: No IDU, tattoos, transfusions . ETOH-positive,
unprotected sex with prostitutes.
 Physical exam: RUQ tenderness, tender liver edge at
RCM, scleral icterus
 T. Bili – 14.2, AP – 130, AST- 1565, ALT – 2448, GGT –
287, T.P. – 7.1, Alb. – 4.4, LDH – 541
 INR – 1.1
 Serology: HAV IgM – NR, HBsAg – Reactive, anti-HBc
IgM – reactive, anti-HCV - NR

7. CHRONIC HEPATITIS B

8. Slide 7
Natural history of HBV

9. Interpreting HBV Serologic Tests
Centers for Disease Control and Prevention. MMWR. 2008;57(RR08):1-28.
HBsAg HBsAb Total HBcAb IgM HBcAb Interpretation
- - - -
Never infected/ not
immunized
+ - + -
Chronic
( active, inactive carrier
and immune tolerant)
+ - - + Acute infection
- + + -
Past infection with
immunity(Resolved)
- + - - Immune

10. Slide 8
Immune
escape
< <> >
HBeAg+ve HBeAg–ve
ALT
HBV-DNA
Inactive (carrier)
state*
HBeAg –ve active
chronic hepatitis
HBeAg +ve
chronic hepatitis
Immune
tolerance
Immune
clearance
Immune
control
The phases of chronic hepatitis B
*Previously considered to be ‘healthy carriers’

11. Case study 3
 26 year old woman presents to liver clinic after undergoing community
screening for viral hepatitis
 Family HX: She is of Laotian descent; two older siblings have
hepatitis B
 Physical exam: BMI 22, normal
 T. Bili 2.2 Direct bili 0.2, ALP 90, AST 18, ALT 14, Alb 4.2
 INR – 0.9
 Serology: HBsAg – Reactive, anti-HBc – reactive, HbeAg positive,
Hbeab negative, HBV DNA >200,000
– What is the most appropriate step?
• Liver biopsy
• Immunize against HBV
• Monitoring transaminases,
• Tenofovir
 Adapted from MKSAP 16

12. Slide 11
Who should be considered for treatment?
Immune
escape
< <> >
HBeAg+ve HBeAg–ve
ALT
HBV-DNA
Inactive (carrier)
state
HBeAg –ve/+ve active
chronic hepatitis
HBeAg +ve
chronic hepatitis
Immune
tolerance
Immune
clearance
Immune
control
treat treat

13. Slide 12
Overview of Algorithm Used to Determine
Need for Treatment of HBV
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008
Lok AS et al Hepatology, 2009
HBeAg Positive
Treat
Monitor ALT
Q3mos for 1y
HBeAg Negative
HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL
Normal ALT
Consider Liver
Biopsy >40 yrs
Significant fibrosis or
inflammation
Elevated ALT
ALT Level

14. Slide 13
Approved HBV treatments 2009
• Interferon alfa-2b – 1991
• Lamivudine – 1998
• Adefovir – 2002
• Entecavir – 2005
• Peginterferon alfa-2a – 2005
• Telbivudine – 2006
• Tenofovir - 2008
For HIV:
o Emtricitabine
o Tenofovir + emtricitabine (single pill co-formulation)

15. Vaccination Recommendations
• Sexual and household contacts of HBsAg carriers
• Newborns of HBV-infected mothers - HBIG and HBV vaccine series
(begin at delivery)
• Infants of HBsAg-positive mothers, health care workers, HD
patients, and sexual partners of carriers
• Post-vaccination testing – Infants-age 9 to 15 mos.
• 1-2 mos after the last dose in others
• Follow-up testing of vaccine response -annually for HD patients
• Persons who are positive only for anti-HBc and who are from a
low endemic area with no risk factors for HBV should be given
the full series of hepatitis B vaccine.
• Lok and McMahon, AASLD guidelines

16. Hepatitis Vaccine- Typical Schedule
 Hepatitis Vaccines
– Hep A and B (Twinrix)
• Three doses (0.5 mL) at 0, 1 and 6 months
– Hep B (Engerix-B or Recombivax)
• Three doses- (1 mL) at 0, 1, and 6 months
– Engerix contains 20 mcg/mL
– Recombivax contains 10 mcg/mL

17. Slide 32
Reactivation of HBV
• High rate of reactivation in
immunosuppressed patients
o Chemotherapy
o HIV after immune reconstitution
o Post organ transplant
o Biologic response modifiers: rituximab (anti-
CD20), TNF-inhibitors: GI, hematologists,
rheumatologists, dermatologists

18. Slide 33
Reactivation of HBV
• ALL patients undergoing chemotherapy must
have tested HBsAg, HBsAb and HBcAb prior
to treatment

19. Slide 36
Require monitoring…
• Inactive disease may not remain inactive
• Liver damage may occur if HBV
reactivates
Require treatment
40%
60%
HBV is a dynamic disease!!!
HBV can be controlled
HBV: The importance of monitoring

20. Hepatitis C
http://www.hcvguidelines.org

21. Question 1
 Which of the following statements is TRUE regarding the
epidemiology of chronic hepatitis C virus (HCV) infection
 A. The prevalence of chronic HCV has risen between 1990-
2000 and 2001-2010
 B. Blood transfusions before 1992 represent the most
common route of transmission
 C. The burden of chronic HCV is higher in North America
than the sub-Saharan Africa
 D. The prevalence of chronic HCV is highest in US adults
born between 1945-1965
 E. Approximately 5-10% of individuals with HIV also harbor
chronic HCV infection
Adapted from DDSEP 7

22. Question 2
 52 year old woman presents to your office for the management of
chronic hepatitis C infection. Laboratory testing reveals: HCV
genotype 2a, HCV RNA 1.63 million IU/ml, AST 59 U/L, ALT 78 U/L,
Albumin 4.3 g/dL, INR 0.9 Hgb 13.1 and platelets 125,000. She is
treatment naïve and expresses interest in pursuing antiviral therapy.
Which one of the following statements is correct?
 A. She will require a liver biopsy prior to consideration for antiviral
therapy
 B. The standard of care treatment is sofosbuvir 400 mg daily and
weight based ribavirin twice daily.
 C. The standard of care treatment is protease inhibitor based triple
therapy
 D. The standard ribavirin dosing is based on patient body weight
(600mg/day if body weight<= 75 g, 1200 mg/day if body weight>75kg
E. The standard duration of antiviral therapy is 24 weeks
Adapted from DDSEP 7

23. Background
 The hepatitis C virus (HCV) with an estimated 180
million people infected worldwide is a leading cause
of chronic liver disease.
 The prevalence of HCV infection in the U.S has
been estimated at 1.6%, equating to about 4.1
million persons positive for the hepatitis C antibody

24. Screening Recommendations
• Annual HCV testing
• Persons who inject drugs, HIV seropositive men who have
unprotected sex with men and ongoing risk factors
• One time Testing
• Asymptomatic adults born between 1945 through 1965
• Persons with conditions associated with a high prevalence
• Hemodialysis
• Abnormal aminotransferases
• Recipients of transfusions/organ transplants before 1992
or clotting factor concentrates before 1987
• Children born to HCV-infected mothers
• Tatoos or ever incarcerated
• AASLD/IDSA Guidelines 02/24/2014
• CDC guidelines 2012

25. Recommendations Prior to Therapy (AASLD/IDSA 2014)
 Quantitative HCV RNA and genotype
 Education/interventions – liver disease progression and transmission
– Conditions that may accelerate liver fibrosis
• Alcohol
• HBV and HIV
– Advanced fibrosis by liver biopsy, imaging or noninvasive markers
– Vaccination against HAV and HBV
 Evaluation by an health care provider
– Comprehensive management
– Antiviral therapy evaluation
AASLD/IDSA Guidelines 02/24/2014

26. Recommendations on Who To Treat (AASLD/IDSA 08/14)
 Reduce all-cause mortality and liver-related ESLD and HCC
 Treatment is recommended
– Highest priority for those patients with
• advanced fibrosis (Metavir F3)
• compensated cirrhosis (Metavir F4)
• TX recipients, and patients with severe extrahepatic HCV
Prioritize patients with high risk for liver-related complications and
severe extrahepatic hepatitis C complications
AASLD/IDSA Guidelines 08/24/2014

27. Hepatitis C Virus
 Hepatitis C Virus
– Member of Flaviviridae family of
spherical, enveloped, positive-
strand RNA viruses
– Six genotypes - geographic
variance
 Hepatitis C Virus Proteins
– Envelope glycoproteins E1-E2
– Protease assembly
NS3/NS4A complex
– NS5A RNA replication assembly
– RNA dependent RNA
polymerase
Moradpour D, Nature Review/Microbiology 2007 5:453

28. Translation and
polyprotein processing
NS3/4
protease
inhibitors
HCV Life Cycle and Targets for
Direct-Acting Antivirals (DAAs)
Receptor binding and
endocytosis Transport
and release
Virion
assembly
RNA replication
Fusion and
uncoating
(+) RNA
Membranous
web
NS5B polymerase
inhibitors
Nucleos(t)ide
Non-nucleoside
NS5A inhibitors
replication and assembly
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

29. Direct Acting Antivirals (DAA)
• Ledipasvir/Sofosbuvir (Harvoni)
• Ombitasvir, Paritaprevir/ritonavir + Dasabuvir
(Viekira Pak)

30. Hepatitis C Viral Replication
1 2 3
456
NS3/4A
Protease
inhibitor

31. Protease Inhibitors
 Simeprevir (Olysio)
– HCV serine protease inhibitor-
inhibition of a protein essential
for viral replication through
cleavage of the viral
polyprotein
– HCV genotype 1
– 1 tablet (150 mg) po qd
 Side Effects
– Photosensitivity
– Hyperbilirubinemia
J Med Chem. 2014. 57:1673-93
Nature Reviews Gastro & Hep 2013 10:596-606 .

32. Hepatitis C Viral Replication
1 2 3
456
Polymerase Inhibitors

33. NS5B Nucleotide polymerase inhibitor
 Sofosbuvir (Sovaldi) (PSI 7977)
– HCV-specific nucleotide
polymerase inhibitor
• Mimics the natural
substrates of the RNA
dependent RNA
polymerase -
incorporated into the
elongated RNA
• Act as chain terminator
– 400 mg qd
 Side Effects
– Insomnia, GI effects
Sofia MJ. J Med Chem. 2010. 53:7202-18
Nature Reviews Gastro & Hep 2013 10:596-606

34. NS5B Non-Nucleoside Polymerase Inhibitors
 Dasabuvir (ABT 333) ( 250mg bid)
– Non-nucleoside analogue inhibitor
• Compound that binds to an
allosteric enzyme site, rending
a conformational protein
change before the elongation
complex is formed
 Side Effects
– Increase bilirubin /transaminases
in combo - ABT450-
Ritonavir/Ombitasvir and RBV
Vermehren J, Clin Microbiol Infect. 2011. 2:122-34
Nature Reviews Gastro & Hep 2013 10:596-606

35. NS5A Replication Complex inhibitors
 Daclatasvir (BMS 790052)(60mg qd)
– Genotype 1, 2, 3
– Combo – Sofosbuvir
 Ledipasvir (GS-5885) (90 mg qd)
– Genotype 1
– Combo - Sofosbuvir
 Ombitasvir (ABT 267)
– Pan-genotypic HCV inhibitor
against GT1-6
– Combo - Paritaprevirwith ritonavir
(R) and dasabuvir
Taylor JG, J Med Chem. 2014. 57:2033-46.
DeGoey DA J Med Chem. 2014. 57):2047-57
Ledipasvir

36. CLINICAL TRIALS
http://www.hcvguidelines.org

37. Trials with New Direct Acting Antiviral Agents
Neutrino
Fission-Fusion
Positron
Electron
Quest/Promise
Cosmos
ION-1
ION-2
ION-3
ALLY
Sapphire
Turquoise
Pearl
HCV

38. Combination Direct Acting Antiviral Therapy
Type Clinical
Trial
Combination Genotypes IDSA/AASLD
Recommend
NS5B
nucleoside
polymerase
Inhibitor
Sofosbuvir FISSION/
FUSION
Ribavirin GT2/3 YES
COSMOS Simeprevir GT1 YES
ION Ledipasvir GT1 YES
ALLY Daclatasvir GT1/2/3 NO

39. 14/38
5/26
Sofosbuvir/Ribavirin – HCV GT2 and GT3
Sofosbuvir/Ribavirin and PegIFN – HCV GT1 and 4-6
No Cirrhosis vs Cirrhosis: SVR12 No cirrhosis Cirrhosis
GT 3GT 2GT 1, 4-6
251/273
43/54
58/59 85/92 25/26 23/23 89/145 57/84 25/40
10/11 16/17 6/10 7/9 13/38 3/14 14/23
Mangia A et al. The Liver Meeting 2013
SVR12(%)

40. COSMOS TRIAL
Simeprevir plus sofosbuvir
with or without ribavirin in
genotype 1
Cohort 1 Treatment naïve
and null responders with
Metavir F0-2
Response rates 93-96%
Cohort 2
Genotype 2, treatment-naïve
and null responder patients
Cirrhosis- 47% of pts
Cohort 2

41. Trials with New Direct Acting Antiviral Agents
Neutrino
Fission-Fusion
Positron
Electron
Quest/Promise
Cosmos
ION-1
ION-2
ION-3
ALLY
Sapphire
Turquoise
Pearl
HCV

42. Sofosbuvir/Ledipasvir – HCV GT 1, Naïve Pts - ION-1
 Phase 3 trial – US
 Fixed dose combination
composed of SOF
(400mg) and LDV (90mg)
w or w/o RBV for 12 or 24
wks
 N=865
 15.7% pts w/ cirrhosis
0
10
20
30
40
50
60
70
80
90
100
SOF/LDV + RBVV
SVR 12

43. Sofosbuvir/Ledipasvir GT 1, Treatment-Experienced Pts - ION-2
 Phase 3 trial - US
 Fixed dose combination
composed of SOF and
LDV w or w/o RBV for 12
or 24 wks
 N=440
 20% pts w/ cirrhosis
0
10
20
30
40
50
60
70
80
90
100
Sof/LDV+
RBV
SOF/LDV+
RBV
SOF/LDV
---12 Wks--- ---24 Wks ---
SVR 12

44. Sofosbuvir/Ledipasvir in GT 1
Treatment-Naïve Patients - ION 3
 Phase 3 trial in U.S.
 FDC - Sofosbuvir and
ledipasvir w or w/o
ribavirin - 8 or 12 wks
 N=647
 No cirrhotic patients 8 weeks 12 weeks
SOF/LDV SOF/LDVSOF/LDV
/RBV
94% 93 % 95%

45. Sofosbuvir and Daclatasvir Naïve and Treatment experienced (ALLY)
 Patient Cohort
– HCV GT1 Naive (n=44) GT 2/3 (n=44)
• Regimen
– Daclatasvir + sofosbuvir w/wo RBV-
24 wks.
 Patient Population
– 123 more GT1
• Regimen
– Daclatasvir + sofosbuvir, w/wo RBV-
12 wks (82 naïve ) or 24 wks (41 pts
exp with PR/T or B
 Results
– 211 pts
•GT1 naive (n=126) - 98%
•GT 1 PR/T/B experienced (n=41) - 98%
• GT 2 (n=26) – 92%
• GT 3 (n=18) - 89%
Side effects – Fatigue/ HA/nausea
98% 92% 89% 97%
GT1 GT2 GT3 GT1/
PI fail

46. Trials with New Direct Acting Antiviral Agents
Neutrino
Fission-Fusion
Positron
Electron
Quest/Promise
Cosmos
ION-1
ION-2
ION-3
ALLY
Sapphire
Turquoise
Pearl
HCV

47. HCV GT 1a/1b patients Naïve and Treatment Experienced (Turquoise II)
 Patient Cohort
– HCV cirrhosis (n=380)
 Regimen – 12 wks or 24 wks (3D
Regimen) (RBV)
– Paritaprevir/ritonavir
– Ombitasvir
– Dasabuvir + RBV
Results
 191/208 - 12 wks - SVR12 - 91.8%
 165 /172 - 24 wks - SVR12 - 96%
 Adverse events
– Fatigue, headache, nausea
– Hgb< 10 g/dL in 7.2% and 11.0%
– Discontinue rate 2.1%
Poordad et al NEJM, 370: 1973-82.

48. AASLD/IDSA HCV Treatment Guidelines- Naïve
Genotype Recommended Alternative
1a
1b
No Cirrhosis:
LDV/SOF x12 wks
OBV/PTV/r + DSV + RBV x12 wks
With Cirrhosis:
LDV/SOF x12 wks
OBV/PTV/r + DSV + RBV x24 wks
No Cirrhosis:
LDV/SOF x12 wks
OBV/PTV/r + DSV x12 wks
With Cirrhosis:
LDV/SOF x12 weeks
OBV/PTV/r + DSV + RBV x12 weeks
No cirrhosis
SOF/SMV +/- RBV-12 wks
With Cirrhosis
SOF/SMV +/- RBV -24 wks
Same as 1a
2 SOF + RBV-12 wks
SOF + RBV -16 wks - Cirrhosis
3 SOF + RBV-24 wks SOF + Peg/RBV-12 wks
4 Same as 1a ( only 12 wks) Same as 1a (only 12 wks)
SOF/RBV -24w

49. AASLD/IDSA HCV Treatment Guidelines - Treatment Experienced
Genotype Recommended Alternative
1a
1b
No Cirrhosis:
LDV/SOF x12 wks
OBV/PTV/r + DSV + RBV x12 wks
With Cirrhosis:
LDV/SOF x24 wks
LDV/SOF + RBV x12 wk
OBV/PTV/r + DSV + RBV x24 wks
No Cirrhosis:
LDV/SOF x12 wks
OBV/PTV/r + DSV x12 wks
With Cirrhosis:
LDV/SOF x24 wks
LDV/SOF + RBV x12 wks
OBV/PTV/r + DSV + RBV x12 wks
No cirrhosis
SOF/SMV +/- RBV -12 wks
With cirrhosis
SOF/SMV +/- RBV - 24 wks
2 SOF + RBV-12 wks
SOF + RBV -16 wks - Cirrhosis
SOF + Peg/RBV-12 wks
3 SOF + RBV-24 wks SOF + Peg/RBV-12 wks
4 Same as 1a ( only 12 wks) SOF + Peg/RBV-12 wks
SOF + RBV -24 wks

50. Question 1
 Which of the following statements is TRUE regarding the
epidemiology of chronic hepatitis C virus ( HCV) infection
 A. The prevalence of chronic HCV has risen between
1990-2000 and 2001-2010
 B. Blood transfusions before 1992 represent the most
common route of transmission
 C. The burden of chronic HCV is higher in North America
than the sub-Saharan Africa
 D. The prevalence of chronic HCV is highest in US adults
born between 1945-1965
 E. Approximately 5-10% of individuals with HIV also
harbor chronic HCV infection
Adapted from DDSEP 7

51. Question 2
 32 year old woman presents to your office for the management of chronic
hepatitis C infection. Laboratory testing reveals: HCV genotype 2a, HCV
RNA 1.63 million IU/ml, AST 59 U/L, ALT 78 U/L, Albumin 4.3 g/dL, INR 0.9
Hgb 13.1 and platelets 276,000. She is treatment naïve and expresses
interest in pursuing antiviral therapy. Which one of the following statements
is correct?
 A. She will require a liver biopsy prior to consideration for antiviral therapy
 B. The standard of care treatment is sofosbuvir 400 mg daily and weight
based ribavirin twice daily.
 C. The standard of care treatment is protease inhibitor based triple therapy
 D. The standard ribavirin dosing is based on patient body weight (600mg/day
if body weight<= 75 g, 1200 mg/day if body weight>75kg
E. The standard duration of antiviral therapy is 12 weeks except in patients
with cirrhosis of 24 weeks is recommended
Adapted from DDSEP 7

52. Summary
 Acute
– Hepatitis A
• HAV IgM, More severe disease with advancing age. Effective vaccine
– Hepatitis B
• HBsAg, HBcIgM,
 Chronic
– Chronic HBV
– HBc Ab Total, HBsAg
• High HBV VL in HBeAg +/Lower HBV VL in HBeAg -
• First line treatment Tenofovir and Entecavir
• Goal -Reduce viral levels <10 IU
– Chronic HCV
• Effective Therapy
– SOF/RBV - GT 2 and 3
– LDV/SOF + RBV –GT1 and 4
– OBV/PTV/r + DSV + RBV - GT1a and GT1b