Hepatitis B and C are caused by viruses that infect the liver and can lead to chronic liver disease and cancer; they are responsible for over 80% of liver cancer worldwide. The hepatitis B and C viruses establish infection stealthily to avoid immune detection, causing both acute and chronic liver inflammation and damage. Effective monitoring and treatment is needed for those with chronic hepatitis B or C infection to prevent progressive liver disease.

1. Hepatitis B & C
A quick update
Prof Siham Abdelrehim
Faculty Of Medicine / Alexanderia Univ
sihamrehim@yahoo.com

2. Impact of Hepatitis
Hepatitis can be caused by:
Harmful consumption of alcohol
Some chemicals and drugs
Viruses – 5 known A, B, C, D & E
Inflammation of the liver – natural
response to injury
Scar tissue = Fibrosis
Extensive scarring = Cirrhosis
HBV & HCV require long term monitoring

3. One in 12 people worldwide are
living with chronic hepatitis B or C
World Hepatitis Alliance
Chronic hepatitis B & C are responsible for over
80% of the worlds liver cancer (HCC)
ASHM/NSWCC 2008

4. Hepatitis B and Hepatitis C: Stealth and
Cunning
The hepatitis B virus (HBV) and hepatitis C virus
(HCV) are:
• noncytopathic
• hepatotropic
• cause acute and chronic necroinflammatory
liver disease and hepatocellular carcinoma
(HCC)

5. Hepatitis B and Hepatitis C: Stealth and
Cunning
•
•
The two viruses could represent very different
antigenic challenges to the immune response, and
this could have an important impact on the outcome
of the infection.
Once infection is established, differences in HBV
and HCV antigenic burden could also have an
impact on viral clearance. In particular, it has been
shown by the use of highly sensitive and specific
immunohistochemical reagents that HBV can infect
up to 100% of the hepatocytes

6. Hepatitis B and Hepatitis C
•
It is widely believed that the outcome of both
infections and the pathogenesis of the associated
liver diseases are determined by host-virus
interactions mediated by the immune response.

7. Hepatitis B and Hepatitis C
•
•
HBV is a stealth virus that establishes itself very
efficiently without alerting the innate immune
system to its presence, although it is readily
controlled when the adaptive immune response is
induced.
In contrast, HCV strongly induces yet cunningly
evades the innate immune response and also
defeats the adaptive immune response by
mutation and functional inactivation

8. Hepatitis B and Hepatitis C
•
Although host factors contribute importantly to
the outcome of HBV and HCV infection, viral
factors are also critically involved. Perhaps the
strongest evidence that viral factors play a role in
the outcome of HBV and HCV infection is that
more than 95% of adult-onset HBV infections are
self limited, while more than 70% of adult-onset
HCV infections persist.

9. HBV
• HBV is a dynamic disease ,changes over time
• Risk of end stage liver disease and cancer
increases with ongoing inflammation and
viremia in adults
• Reactivation can occur even in those who have
lost HBsAg

10. Case presentation
20 year old student with no significant past medical history is
referred for evaluation of HBsAg positivity
She is fit and healthy and asymptomatic
She denies a history of blood transfusion or intravenous-drug
use.
Her mother was diagnosed with hepatitis B and end stage of
liver disease 8 months ago.

11. Case presentation
On Examination
No stigmata of CLD
Abdomen: soft, non-distended, non-tender, liver
edge smooth, liver span 8 cm by percussion, no
splenomegaly
Blood
HBsAg: positive
Hepatitis C virus (HCV) antibody (Ab): negative

12. Which of the following blood tests would provide the most useful
information to characterize the status of chronic hepatitis B and
guide recommendations regarding antiviral therapy?
A)HBeAg, HBsAb, and hepatitis B core antibody (HBcAb)
B) HBeAg, HBeAb, and HBV genotype
C) HBeAg, HBeAb, HBV DNA viral load, and HBs Ag level
D) HBeAg, HBeAb, and HBV DNA viral load

13. Which of the following blood tests would provide the most useful
information to characterize the status of chronic hepatitis B and
guide recommendations regarding antiviral therapy?
A)HBeAg, HBsAb, and hepatitis B core antibody (HBcAb)
B) HBeAg, HBeAb, and HBV genotype
C) HBeAg, HBeAb, HBV DNA viral load, and HBs Ag level
D) HBeAg, HBeAb, and HBV DNA viral load

14. The Emerging Role of HBV Genotypes
There are 8 genotypes of hepatitis B (A through H)
Although it is not routine, it may assume a role in the
management of hepatitis B
Clear association with:
Precore/core promoter mutations
Rates of HBeAg clearance
Development of HBeAg-neg Chronic Hepatitis B

15. HBV Genotypes May Have Clinical Implications
F
D
B – Earlier appearance of
HBeAg antibodies and
slower progression (vs
C)
A,B,C,
A – Higher
rates of
sustained
treatment
response
A,G
D,G
Anti-e-positive
chronic hepatitis B
and cirrhosis
Dhigher than in A
D
C
D
D
E
D
Ba
F
F
H
Bj
C
A
A,B,C,D
C – Liver disease more
severe than in B,
associated with HCC
Adapted from Fung SK et al. Hepatology. 2004;40:790-792.
Copyright © 2004, American Association for the Study of Liver Disease.
Reproduced with permission of John Wiley & Sons, Inc.

16. Back to the case
Which of the following blood tests would provide the most useful
information to characterize the status of chronic hepatitis B and
guide recommendations regarding antiviral therapy?
A)HBeAg, HBsAb, and hepatitis B core antibody (HBcAb)
B) HBeAg, HBeAb, and HBV genotype
C) HBeAg, HBeAb, HBV DNA viral load, and HBs Ag level
D) HBeAg, HBeAb, and HBV DNA viral load

17. Case presentation
Further Blood results
AST ↑ 95 U/L
ALT ↑ 132 U/L
ALP N 121 mg/d
Bilirubin N
HBeAg: negative
HBeAb: positive
HBV DNA: 400,000 IU/mL

18. What is the significance of HBeAg -ve
CHB?
• Clinically silent for years
• Severe necroinflammation in >50%, cirrhosis in
25-40%
• Rare spontaneous sustained remission
• Fluctuations in viraemia and ALT
• HBV DNA may be persistently < 105 copies/mL
but yet has significant liver disease

19. Which statement is false regarding this patient's hepatitis B
status?
1.She is an inactive carrier of hepatitis B
2.She is not in the immune-tolerant phase
3. She likely has a mutation in the precore or core promoter
region of the HBV genome
4.HBeAg positivity is associated with a better prognosis than
HBeAg negativity

20. Which statement is false regarding this patient's hepatitis B
status?
1.She is an inactive carrier of hepatitis B
2.She is not in the immune-tolerant phase
3. She likely has a mutation in the precore or core promoter region
of the HBV genome
4.HBeAg positivity is associated with a better prognosis than
HBeAg negativity

21. Which statement is false regarding this
patient's hepatitis B status?
HBeAg
Anti-HBe
HBV-DNA
ALT
immune
tolerance
immune
clearance
inactive
carrier
reactivation

22. NIH Definition of Inactive HBsAg Carrier
•
Presence of HBsAg and anti-HBe in serum
•
Serum HBV DNA < 105 copies/ml
•
Persistently normal serum ALT > 6 months
•
Liver histology (not essential) HAI grade < 3

23. Patient's hepatitis B status
HBeAg
Anti-HBe
DNA
HBV-DNA
ALT
immune
tolerance
Treat
immune
clearance
inactive
carrier
reactivation
Treat
Who should be considered for treatment?

24. What level of HBV DNA would you start
treatment?
a. HBV DNA ≥ log 10 4
b. HBV DNA ≥ log 10 5
c. Any level of HBV DNA

25. HBV Treatment Guidelines
HBeAg
+
+
+
–
–
–
HBV DNA
(IU/ml)*
ALT
Management
< 20,000
Normal#
Follow, no treatment
≥ 20,000
Normal
Consider biopsy;
treat if diseased
≥ 20,000
Elevated
Treat
< 2,000
Normal
Follow, no treatment
≥ 2,000
Normal
Consider biopsy;
treat if diseased
≥ 2,000
Elevated
Treat
*1 IU = 5.6 copies; # Normal ALT for men = 30 U/ml and for women = 19 U/ml
Keeffe EB, et al. Clin Gastroenterol Hepatol.2006.

26. What level of HBV DNA would you start
treatment?
a. HBV DNA ≥ log 10 4
b. HBV DNA ≥ log 10 5
c. Any level of HBV DNA + ALT elevated
≥ 2,000 c/ml
IU = 5.6 copies

27. Evolution of Chronic HBV Therapy Over Time
Peginterferon alfa-2a
Entecavir
Lamivudine
1990
Interferon alfa-2b
1998
2002
Adefovir
2005
Tenofovir
2006
Telbivudine
2008

28. Treatment
Nucleoside Analogues -- Lamivudine, Entecavir
•
Lamivudine
• Dose : 100 mg PO q daily
• Good for reducing the risk of progression to hepatic decompensation in
patients with cirrhosis or advanced fibrosis
• Pregnancy category B--Not teratogenic in animal studies and successful
use with pregnant women
• Problem: High rates of resistant mutations
• Side effect: lactic acidosis
•
Entecavir – 1st line
• 0.5 to 1mg PO
• very effective; low resistance and greater than 90% HBV DNA clearance
rate in HBeAg positive pts
• Side effect: lactic acidosis

29. Treatment cont.
Nucleotide analogues
•
Tenovir
• Dose: 300mg qd
• Highly effective with low resistance
• Well tolerated
•
Adefovir – 1st line
• Dose: 10mg daily
• Resistance less than Tenovir
• Side effect: nephrotoxicity and lactic acid

30. NAs: Potency versus resistance
More potent than Adefovir
Nucleoside analogue
Nucleotide analogue
TDF
ETV
LdT
LAM
ADV
Potency of HBV DNA suppression
Likelihood of resistance
development

31. HBV life cycle
Neutralizing antibodies
(HBsAg-specific)
Hepatocyte-specific receptor
Nuclear steps require liver-specific
elements
Reverse transcription
Essential for virion
formation
Integration NOT essential
(contrast to
retroviruses)
HBV polymerase inhibitors
(Lamivudine, Adefovir, Entecavir,Tenofovir)

32. Back to the case
What is the most appropriate management
strategy at this time?
A) Start lamivudine 100 mg once daily
B) Start adefovir 10 mg once daily
C) Start entecavir 0.5 mg once daily
D) Start Tenofovir 300 mg
E) Observation; follow liver function tests every 3
months for 1 year

33. What is the most appropriate management
strategy at this time?
A) Start lamivudine 100 mg once daily
B) Start adefovir 10 mg once daily
C) Start entecavir 0.5 mg once daily
D) Start Tenofovir 300 mg
E) Observation; follow liver function tests every 3
months for 1 year

34. She received lamivudine continuously
After 6 ms her laboratory studies were as follows:
AST
N
ALT
N
HBV DNA
-ve

35. What are your recommendations at this time?
A) Continue to follow serum aminotransferases and HBV DNA levels at
6 months intervals
B) Continue lamivudine 100 mg once daily for at least 3 years after HBV
load is undetectable
C) Given that the HBV load is undetectable, her disease is classified as
inactive and she no longer needs regular follow-up at all.
D) Given that the HBV load is undetectable, she needs regular follow
HBsAg level

36. What are your recommendations at this time?
All except
A) Continue to follow serum aminotransferases and HBV DNA levels at
6 months intervals
B) Continue lamivudine 100 mg once daily for at least 3 years after HBV
load is undetectable
C) Given that the HBV load is undetectable, her disease is classified as
inactive and she no longer needs regular follow-up at all.
D) Given that the HBV load is undetectable, she needs regular follow
HBsAg level

37. She has now been on lamivudine continuously for more
than 2 years
Her most recent laboratory studies were as follows:
AST
N
ALT
N
HBV DNA
-ve
HBsAg titre 54320

38. qHBsAg can predict spontaneous HBsAg loss
in HBV carriers
Serum HBsAg level <100 IU/ml at 1 year post-HBeAg
seroconversion can predict HBsAg loss within 6
years1
HBsAg <10 IU/ml is the strongest predictor of HBsAg
loss in HBeAg-negative patients who have HBV
DNA <2000 IU/ml2
Decreasing HBsAg level (<200 IU/ml or a decrease of
≥ 1 log 10 IU/ml) can predict HBsAg seroclearance
in inactive CHB patients3
1. Tseng, Kao et al. Gastroenterology 2011
2. Tseng, Kao et al. Hepatology 2012
3. Chen YC, et al. Clin Gastroenterol Hepatol 2011

39. HBsAg level is an important risk factor in patients
with low HBV DNA level (<2000 IU/mL)
ERADICATE-B (2688 HBV carriers)
5-fold risk increase
by univariate analysis
Tseng, Kao. Gastroenterology 2012; Chan HL. Gastroenterology 2012

41. HBV DNA, HBsAg and ALT levels during different
phases of CHB
Janssen et al. Gut 2012.

42. The case
• She was continued on lamivudine. After 36 months
HBV DNA below detectable levels. ALT 20 U/l
• Well until 6 months later her ALT 90 U/l
• Repeat HBV DNA 6,000 IU/ml
• What is the cause for her virologic and biochemical
breakthrough?

44. Extended LAM therapy in HBeAg(-) CHB:
The Italian experience (616 patients)
100
Virological response 1
89%
Virological Breakthrough2
80
% patients
63%
61%
60
37%
40
20
0
48% 52%
39%
11%
1 year
2 years
3 years
4 years
Virological Response to LAM (4 Years): Resistance Exceeds Efficacy
1 HBV DNA < 105 copies/mL
2 Re-appearance of HBV DNA > 105 copies/mL

45. Rise in serum
transaminases
Worsening of liver disease

46. Once Viral Resistance has developed
Add or Switch?
Should we continue or stop the lamivudine? If
continue for how long?
Besides lamivudine, are there any other
options?

47. What treatment options for lamivudine
resistant ?
a. switch to adefovir
b. lamivudine combines with adefovir
c. switch to entecavir
d. switch to interferon

48. Rescue Therapy for AntiviralResistant HBV
•
•
•
•
Lamivudine-R
• Add adefovir/tenofovir
• Switch to tenofovir or switch to entecavir (risk of
subsequent entecavir-R)
Adefovir-R*
• Add lamivudine or switch to tenofovir
• Switch to entecavir (if no prior LAM-R)
Entecavir-R*
• Add or switch to adefovir or tenofovir
Multidrug R → ???

49. Back to the patient
•
•
•
•
Started on tenofovir 300mg /d
Seen by me every 6 ms ALT 49 -ve DNA , HBsAg 5000
Any mistakes in treatment?
What medication should we use next?

50. HBV Control
Inflammatory: normalize serum ALT.
Virologic: decrease HBV DNA.
Immune: seroconversion
HBeAg to HBeAb
HBsAg to HBsAb
HBV never “cured” but controlled

51. Therapeutic endpoints over time
Improved
histology
Anti-HBe+
Loss of
HBeAg
Loss of
HBV DNA
TIME
Anti-HBs+
Loss of
HBsAg

52. Antiviral Treatment of HBeAg (+)
mild-moderate liver disease
ALT > 2 ULN and/or histology > F1
Lamivudine/Adefovir/Entecavir/Tenofovir
HBeAg seroconversion?
No
ALT normal?
Yes
Continue therapy
Yes
Continue treatment
for at least 6 months
No
Drug resistance ?

53. Antiviral Treatment of HBeAg (-)
mild-moderate liver disease
ALT > 2 ULN and/or histology > F1
Lamivudine/Adefovir/Entecavir/Tenofovir
ALT normal
Yes
Continue treatment
indefinitely
No
ALT↑
Drug resistance ?

54. Treat Today
To Prevent Tomorrow

55. HBV Prevention
•
Active immunization
• Recombinant subunit vaccine produced in yeast (HBsAg)
• Combination vaccine with HAV available (Twinrix)
• Highly effective
• Component of routine childhood vaccine series
• Recommended for high risk adults
• Health care and long-term care facility workers, HD patients, IVDU,
travelers, chronic liver disease
• Seroconversion rate declines with age and immunosuppression
•
•
>95% for age < 30 yo, but only 50% for age > 60 yo
Passive immunization
• Immune globulin available for post-exposure prophylaxis

56. IgG HBcAb????
A hepatitis panel is ordered for a 27 year old female as part
of a routine workup for abdominal pain.
Results of serological testing a negative for HBeAg and
HBsAg, but positive for IgG HBcAb.
The patient has been exposed to Hep B.
a.
b.
c.
d.
e.
Patient has recovered
Patient is in acute infective disease state
Window period
Chronically infected
Patient was never infected

57. THANK YOU

58. Hepatitis C virus (HCV)



Family: Flaviviridae
Enveloped
Non-segmented positive (+) strand RNA genome
Cambridge University Press

59. HCV Clinical Manifestations
 Transmission
– IVDU, sexual (less than HBV), transfusion, transplant
– Vertical
 Primary symptoms
– Acute infection often asymptomatic
– Only 20% clear infection (contrast with HBV)
 Complications
– 70-80% progress to chronic infection
– 20% will develop cirrhosis (over 20 years)
– HCC risk increased (1-4% per year)
– Extrahepatic manifestations
– Mixed cryoglobulinemia

60. HCV Diagnosis and Treatment
 Diagnosis
– Serologies
– Viral genome detection (RT-PCR)
 Treatment
– Interferon α (frequent adverse reactions)
– Ribavirin
– Rapid resistance if use alone
– Combination therapy most effective (IFN α + Rib)
– <50% sustained response
– Active area of investigation for new targets/drugs
– R7128 and IDX184 - polymerase inhibitors
– VX-950 (Telaprevir) - protease inhibitor
– Debio-025 – cyclophilin inhibitor
– Liver transplantation