1. Chronic HEPATITIS B Infection
Diagnosis and management
Dr NEERAJ NAGAICH
Dept of gastroenteroloy
SMS medical college jaipur.

2. A world-wide public health problem
• Three quarters of the world’s 5.2 billion people live in endemic
regions
• Nearly 75% of chronic carriers are Asian.
• HBV is 100 times more contagious than HIV.

3. A world-wide public health problem
• Established cause of chronic hepatitis and cirrhosis.
• 2nd most important carcinogen behind tobacco.
• cause of up to 80% of Hepatocellular carcinomas.

4. Geographic Distribution of Chronic
HBV Infection
HBsAg Prevalence
≥8% - High
2-7% - Intermediate
<2% - Low

5. Hepatitis B Immunopathogenesis

6. Natural History

7. Outcome Of Acute Hepatitis B

8. Natural history
>90% of Children
Acute HBV Infection Chronic HBV Infection
<5% of Adults
10% of Children 30-40% Risk
95% of Adults
Hepatocellular
Recovery Cirrhosis
Carcinoma (HCC)
Protective Immunity
Transplant or Death

9. Phases of Infection

10. Phases of Chronic HBV Infection

11. Whom to screen
``` wi
• Patients with elevated liver enzymes
• Patients with HCC, Cirrhosis ,liver fibrosis
• Immigrants from areas of high HBV prevalence
• Families , household members and sexual contacts of HBV + person
• Patients in psychiatric institutions, residents of welfare institutions
and mentally disabled
• Homo/Bisexuals and person having multiple sexual partners
• Active and ex drug user
• Dialysis patients
• HCV or HIV infected persons

12. Whom to screen…
• Recipients of organ transplant before and after transplant
• Blood and organ donors
• All medical personnel's
• All pregnant women
• Patients before and during immunosuppressive or
chemotherapy therapy
• New borne to HBsAg + ve mothers

13. Diagnosis

14. Diagnosis

15. Interpretation of Hepatitis B Panel
HBsAg HBsAg negative negative
antiHBc antiHBc positive immune due to natural infection
negative susceptible
antiHBs positive
antiHBs negative
HBsAg negative
antiHBc negative immune due to vaccine
antiHBs positive
HBsAg positive
antiHBc ( total ) positive acutely infected
IgM antiHBc positive
antiHBs negative
HBsAg positive
antiHBc ( IgG) positive chronically
IgM antiHBc negative infected
antiHBs negative
HBsAg negative 1.resolution of chronic infection
2. “window period” infection
antiHBc ( IgG) positive 3. false-positive anti-HBc
antiHBs negative 4. active infection with waning HBsAg

16. Treatment

17. Goals of HBV Therapy
•HBV infection cannot eliminated or “cured”
•The clinical goal of HBV treatment (primary goal )
Prevention or reversal of complications
/deaths
suppress HBV replication and achieve a target HBV
DNA <10-15 IU/mL
Can allow biochemical remission and prevent further liver
injury

18. Goals of HBV Therapy
In HBeAg-positive patients (cont)
HBeAg loss and seroconversion
In HBeAg-positive and HBeAg-negative patients
HBsAg loss and seroconversion is ultimate form of
HBV treatment success
Best predictor of durable viral suppression
Strongest indicator of best longterm outcome, lowest risk
of cirrhosis and liver cancer
Not achieved by the majority of patients
Histological Improvement

19. Options in treatment

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

21. Recommendations for Treatment
Initiation in HBeAg-Positive Patients
AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]
HBV DNA, IU/mL > 20,000 > 20,000 ≥ 2,000
ALT, x ULN* >2 >1 >1
Moderate/severe necroinflammation
Disease stage/grade
and/or significant fibrosis
ADV,† ETV, ETV, TDF, ETV, TDF,
First-line therapy
pegIFN pegIFN pegIFN
 Criteria for HBV DNA, ALT and disease stage/grade must all be met
– If not, guidelines recommend monitoring and consideration of treatment based on individual’s age,
health status, and stage of infection/disease
1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol.
2008;6:1315-1341. 3. EASL HBV Guidelines. J Hepatology. 2009;50:227-242.

22. Recommendations for Treatment
Initiation in HBeAg-Negative Patients
AASLD 2007[1] US Algorithm 2008[2] EASL 2009[3]
HBV DNA, IU/mL > 20,000‡ > 2000 ≥ 2000
ALT, x ULN* 1 to > 2 >1 >1
Moderate/severe necroinflammation
Disease stage/grade
and/or significant fibrosis
ADV,† ETV, ETV, TDF, ETV, TDF,
First-line therapy
pegIFN pegIFN pegIFN
 Criteria for HBV DNA, ALT and disease stage/grade must all be met
– If not, guidelines recommend monitoring and consideration of treatment based
on individual’s age, health status, and stage of infection/disease
1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3.
EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.

23. Special Populations That Should Also Be
Considered for HBV Treatment
Regardless of HBV DNA and ALT levels
• Patients with rapid deterioration of liver function
• Patients with compensated cirrhosis
If DNA > 2,000 IU/mL, regardless of ALT
• Patients with decompensated cirrhosis (IFN
contraindicated)
• Recurrent HBV infection post liver transplantation
• HBV carriers undergoing immunosuppressive or
cytotoxic chemotherapy

24. Factors Associated With Choosing
Nucleos(t)ides as Initial Therapy
Favorable predictors of response
High ALT
Low HBV DNA (baseline and on treatment)
Specific patient demographics
Older people
Patient preference
Concomitant HIV infection
No HCV coinfection

25. Selecting Between Recommended First
Line Nucleos(t)ide and Interferon Therapy
Nucleos(t)ides Interferon-Based Therapy
Feature Pro Con Pro Con
Long term/
Administration Oral Finite duration Subcutaneous
indefinite
Low durable rates
Antiviral activity High
DNA suppression
Very low
Resistance No
resistance†
Rare renal tox
Adverse events Minimal Substantial*
with nucleotide
HBeAg loss and HBeAg loss ↑ Lower rates vs. Higher rates vs HBeAg loss ≠ HBV
clearance over time IFN nucles(t)ides DNA suppression
HBsAg loss and Higher and High rates (select Low rates in general
Low rates
clearance earlier events† populations) patient groups
May induce HIV
Other Anti HIV (TDF) resistance Anti HCV/HDV
(TDF/ETV)

26. Selecting a First-line Nucleos(t)ide

27. Factors Driving Selection of Initial
Nucleos(t)ide
Safety
Efficacy
(potency)
Barrier to
resistance
(durability)

28. Efficacy (Potency)

29. Undetectable* HBV DNA in HBV Patients
After 1 Year of Treatment
Not head-to-head trials; different patient populations and trial designs
HBeAg Positive HBeAg Negative
100 100
90 88 91
Undetectable* HBV DNA (%)
80 76 80
67
60 60-73
60 60
51-63
40-44
40 40
20 13-21 20
0 0
LAM ADV ETV LdT TDF LAM ADV ETV LdT TDF
*By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies.
Lok A, et al. Hepatology. 2007;45:507-539. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242 .

30. HBeAg Loss/Seroconversion in HBeAg-
Positive Patients After 1 Year of Treatment
Not head-to-head trials; different patient populations and trial designs
HBeAg Loss/Seroconversion (%)
HBeAg Loss HBeAg Seroconversion
100 100
80 80
60 60
40 32 40
24 26 23
22 22 21 21
20 20 12-18
NR
0 0
LAM ADV ETV LdT TDF LAM ADV ETV LdT TDF
Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2003;348:808-816 Chang TT, et al. N
Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med.
2008;359:2442-2455.

31. Normalization of ALT and Histological
Improvement After 1 Year of
Treatment
HBeAg Positive
Outcome, % LAM ADV ETV LdT TDF
Normalization of ALT 41-75 48 68 77 69
Histological improvement 49-56 53 72 65 74
HBeAg Negative
Outcome, % LAM ADV ETV LdT TDF
Normalization of ALT 60-79 72 78 74 77
Histological improvement 60-66 64 70 67 72
Lai CL, et al. N Engl J Med. 1998;339:61-68. Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263.
Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al.
N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Marcellin P, et al.
2008;359:2442-2455.

32. Resistance and
Treatment Durability

33. Cumulative Rates of Resistance With Oral
Agents in Nucleos(t)ide-Naive Patients
LAM ADV ETV LdT TDF
100
80 70
67
Patients (%)
60 49
40 38
29
24
18
20 17 11
4 3 0.5
0 0.2 0 0 1.2 1.2 1.2 1.2
0
1 2 3 4 5 6
Year

34. Summary of Potency and Genetic
Barrier to Resistance
LAM and LdT
Potent agents with low genetic barriers and high rates of
resistance
ADV
Less potent agent with low pharmacologic barrier with
intermediate rate of resistance
ETV
Potent agent with high pharmacologic and genetic barriers and
low rates of resistance
TDF
Potent agent with high pharmacologic and low rates of
resistance, genetic barrier not yet defined

35. Proposed Special Populations for
Combination Therapy
Cirrhosis (especially decompensated)
High risk of hepatitis flare with emergence of resistance
HIV/HBV coinfection
Drugs with dual antiviral activity must be used in
combination to prevent drug resistance
Preexisting resistance
Rates of infection with resistant virus low but increasing
No data showing benefit of combination therapy vs. monotherapy with newer
more potent agents in treatment naïve patients

36. Summary of FDA Approved Oral HBV
Treatments
*Approximate and relative.
†
Number of mutations needed for primary antiviral drug resistance.
‡
Only includes reported adverse events that may differ in historical incidence associated
with LAM and, therefore, potentially affecting selection vs other agents. Pancreatitis has
been reported as a class effect and all agents have to be dose adjusted for renal
insufficiency.
§
From HIV databases

37. Summary: Selecting the Best
Nucleos(t)ide for Initial Therapy
• Use nucleos(t)ides as monotherapy with
•Highest antiviral potency and genetic barrier to resistance
•Low incidence of resistance over time
•LAM/LdT/ADV not generally recommended as first-line therapy
• Combination therapy may be considered in patients where avoiding
resistance is especially important
•Consider individual patient characteristics in relation to safety
•Comorbidities (ie, compromised renal function)
•Coinfections (ie, anti-HIV activity of agents)
•Conception planning

38. Tenofovir Disoproxil Fumarate

39. Tenofovir vs Adefovir
comparison of results at week 48
HBeAg +ve HB e Ag –ve
Tenofovir Adefovir Tenofovir Adefovir
300 mg 10 mg 300 mg 10 mg
176 patients 90 patient 250 Patient s 125 patients
HBV DNA 76% 13% 93% 63%
<400 copies /ml
ALT 68% 54% 76% 77%
Normalization
HBeAg 21 18 -- --
Seroconversion
Histological 74 68 72 69
Response
≥ 2 log fall KS

40. Regression of Fibrosis on ADV
1 year ADV
Fibrosis = 5/6
5 years ADV
Fibrosis = 3/6
Patient 1566 (year 5 cohort)

41. Selecting an Interferon-Based Initial
HBV Treatment

42. Factors Associated With Choosing
Interferon for Initial Therapy
Favorable predictors of response
Genotype A or B > C or D
Low HBV DNA (baseline and on treatment)
High ALT (baseline)
Specific patient demographics
Younger people
Young woman wanting future pregnancy
Patient preference
No coinfection with HIV
Concomitant HCV infection

43. PegIFN Treatment-Associated
Adverse Effects
Patients should be carefully monitored for adverse events
Most common adverse events: flu-like symptoms (fever, chills,
headache, malaise, and myalgia) as well as psychological impairment
Incidence/Severity
Increase in
Depression
Fatigue
Anxiety
Flu-like
symptoms
0 1 2 3 4
Months
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

44. Peglfa-2a vs LAM vs Combination at EOT (48 Weeks) in
HBeAg-Positive Patients
PegIFN 180 µg (n = 271) PegIFN + LAM (n = 271) LAM 100 mg (n = 272)
100
86
80 69
62
Patients (%)
62
60 52
46
40 39
40 30
27 24 27 25
20 22
20
0
HBeAg HBeAg HBV DNA HBV DNA ALT
Seroconversion Loss < 105 copies/mL < 400 copies/mL Normal
(~ 20,000 IU/mL) (~ 80 IU/mL)
 Lau GK, et al. N Engl J Med. 2005;352:2682-2695.

45. HBeAg Seroconversion After EOT
(Week 48)
100
90
Off-Treatment Follow-up (Week 72)
HBeAg Seroconversion (%)
80
70
60
P < .001
50
40 P = .023
32
30 27
20 19
10
0
PegIFN PegIFN + LAM LAM
(n = 271) (n = 271) (n = 272)

46. Viral Suppression in HBeAg-Negative
Patients After PegIFN-2a ± LAM Treatment
100
90
Patients with HBV DNA
≤ 400 copies/mL (%)*
80
70
60
50
40
30
20 18 17
13 13
10
0
1 2 3 4
Years After Therapy Completed
*~ 80 IU/mL, missing data considered a nonresponse.
Marcellin P, et al. AASLD 2006. Abstract. 972. Marcellin P, et al. EASL 2007. Abstract 53.
Marcellin P, et al. EASL 2008. Abstract 103.

47. Early HBsAg Kinetics Are Predictive of
Long-term PegIFN Treatment Success
•HBsAg decrease at Week 12 associated with
subsequent sustained treatment response in both
HBeAg-positive or HBeAg-negative patients
•Suggests that HBsAg monitoring could be
beneficial in identifying
•Patients likely to respond favorably in the long term
•Patients likely to be nonresponders
•Who might benefit from an alternative treatment approach
Lau GK, et al. APASL 2009. Abstract PE083. Moucari R, et al. Hepatology. 2009;49:1151-1157. Brunetto MR, et al.
Hepatology. 2009;49:1411-1150. Moucari R, et al. J Hepatol. 2009;50:1084-1092. Perillo RP. Hepatology.
2009;49:1063-1065.

48. Summary of PegIFN alfa-
2a as Initial Therapy
•Advantages:
• finite duration of treatment, durable response in a subset
of responding patients; lack of viral resistance
development
•Disadvantages:
•administered by subcutaneous injections; associated with
significant toxicities in most patients
•HBeAg and HBsAg seroconversion rates, tolerability, and
likelihood of response to treatment vs nucleos(t)ides all
play a role decision
•HBsAg kinetics may offer a early idea of the likelihood of
response

49. Other Factors to Consider When
Initiating First-line Treatment

50. Recommendations for HBV-Infected
Women Who Desire Pregnancy
Women with mild liver disease, low viremia
Pregnancy before treatment
Women with moderate liver disease, no cirrhosis
Treatment before pregnancy; if response, stop treatment before
pregnancy
Women with advanced liver disease
Treatment before and during pregnancy; continue treatment after delivery
Women with mild liver disease, very high viremia
Treatment in last trimester with “B” category drug
Wedemeyer H, et al. Dtsch Med Wochenschr. 2007;132:1775-1782.
EASL HBV Guidelines. J Hepatol. 2009;50:227-242.

51. Dialysis and Renal Transplantation
Patients
 ADV and TDF have been linked to worsening renal
function and should be used with caution in renally
impaired patients
 No specific renal toxicity associated with entecavir
 Dose-adaptation should be used with any agent
 TDF can be used if dose adjustments are made in
response to changes in GFR
 Monitoring of renal function before and during
therapy particularly important.

52. post-exposure prophylaxis

53. Recommended post-exposure prophylaxis
for exposure to HBV
Vaccination
and antibody
Treatment
response status of Source HBsAg Source HBsAg
exposed workers
Source unknown
+ev -ve
HBIG x 1 and initiate Initiate HB vaccine Initiate HB vaccine
Unvaccinated HB vaccine series series series
Previously vaccinated
Known responder No treatment No treatment No treatment
HBIG X 1 and initiate No treatment If known high risk
Known revaccination source, treat as
non-responder* or HBIG X 2 if source were HBsAg
positive
Test exposed person No treatment Test exposed person
Antibody for anti-HBs for anti-HBs
response 1. If adequate, no 1. If adequate, no
treatment is treatment is
unknown necessary. necessary.
2. If inadequate*, 2. If inadequate*,
administer administer vaccine
HBIG x 1 and booster and
vaccine booster. recheck titer in 1-2
months.
Source: MMWR, June 29 2001, vol 50, RR-11, p22
* A non-responder is a person with inadequate levels of serum antibody to HBsAg (I.e., anti-HBs <10 mIU/mL).

54. Take home message
• Suspect and Diagnose.
• Initial evaluation includes education
o Family and contacts should be tested
• Monitor as status changes over time
• Selection of patients to treat
o Individualize treatment decisions
o Change if no/ poor response
• Long term monitoring
o HCC, special populations, reactivation.

55. Take home message
Prevention is better than cure.

56. THANK YOU

58. Outcomes of chronic Hepatitis B
infection

59. A liver biopsy is indicated in the following scenarios :
 HBeAg-negative and HBV DNA ≥ 20,000 IU/ml and
ALT < 2x ULN
 HBeAg-negative and HBV DNA = 2,000–19,999
IU/ml
 HBeAg-positive and HBV DNA ≥ 20,000 IU/ml and
ALT < 2x ULN and age ≥ 40

60. Comparison of the drugs used in treatment-naive
patients with chronic hepatitis B
100 100
Cost /Y 36,500 73,000 1,09500 41,400

61. On interferon alpha therapy:
Primary non-response is defined as
less than 1 log10 IU/ml decrease in HBV DNA level from
baseline at 3 months of therapy.
Virological response is defined as an HBV DNA
concentration of less than 2000 IU/ml at 24 weeks
of therapy.
Serological response is defined by HBe eroconversion
in patients with HBeAg-positive CHB.

62. On NUC therapy:
Primary non-response is defined as
less than 1 log10 IU/ml decrease in HBV DNA level from
baseline at 3 months of therapy.
Virological response is defined as undetectable
HBV DNA by real-time PCR assay within 48
weeks of therapy.
Partial virological response is defined as a decrease
in HBV DNA of more than 1 log10 IU/ml but
detectable HBV DNA by real-time PCR assay.

65. Monitor HBV patients who are not in treatment.
HBeAg(+) and treatment not indicated:
 ALT every 3–6 months if WNL; ALT every 1–3 months if 1–2x ULN.
 HBV DNA viral load every 6–12 months.
 Liver biopsy if ALT ≥ 2x ULN for 6 months, or if ALT 1–2x ULN for
6 months and age ≥ 40
.
HBeAg(–) and treatment not indicated:
 ALT every 3 months for 1 year; then every 6–12 months.
 HBV DNA viral load if ALT > 1–2x ULN.
 Liver biopsy if persistent ALT elevation or HBV DNA ≥ 2,000 IU/ml.

66. Monitor patients on treatment
.
Monitoring schedule for Nucleos(t)ide Analogues:
 ALT and AST levels every 3–6 months
 HBeAg every 3–6 months (in patients who are HBeAg(+) at start of
treatment)
 HBsAg every 6–12 months (in patients who are HBeAg(–) at start of
treatment)
 HBV DNA viral load every 3 months during first year of therapy; then
every 6 months
 Serum creatinine every 12 weeks while taking adefovir or tenofovir
Monitoring schedule for Interferon alfa:

69. HCV co-infected patients
HBV DNA level is often low or is undetectable and HCV is
responsible for the activity of chronic hepatitis in most patients.
patients should receive pegylated interferon alpha with
ribavirin as for HCV .
SVR rates for HCV are broadly comparable with HCV
monoinfected patients .
potential risk of HBV reactivation during or after clearance of
HCV that must then be treated with NUCs

71. HIV co-infected patients
HIV-positive patients with CHB are at increased risk
of cirrhosis . Treatment of HIV may lead to flares
of hepatitis B due to immune restitution.
The indications for therapy are the same as in HIV-negative
patients,
it is recommended that most coinfected patients be
simultaneously treated for both HIV and HBV de novo.
Tenofovir and emtricitabine (FTC) together, plus
a third agent active against HIV, are indicated.

72. Acute severe hepatitis
95–99% of adults with acute HBV infection will recover
spontaneously and seroconvert to anti- HBs without anti-viral
therapy.
Some patients with fulminant hepatitis or severe protracted
subacute hepatic necrosis may benefit from NUC treatment.
potent drugs with a high barrier to resistance, i.e. entecavir
or tenofovir, should be used.
The duration of treatment is not established.
(at least 3 months after seroconversion to anti-HBs or at least 6
months after Hbe Seroconversion is recommended)