chronic hepatitis b treatment guidelines

1. AASLD GUIDELINES FOR
DIAGNOSIS & TREATMENT OF
CHRONIC HEPATITIS B 2014
DR SREEJITH JR2 MEDICINE

2. • Official recommendations of AASLD on the
treatment of chronic hepatitis B (CHB) virus
(HBV) infection in adults and children
• Multiple systematic reviews of literature were
conducted

3. GRADE APPROACH….
QUALITY OF EVIDENCE
classifies as high, moderate, low & very low
RCT - high quality of evidence
OBSERVATIONAL STUDIES –low
STRENGTH OF A RECOMMENDATION
classifies as strong & conditional

4. OBJECTIVES
• Primarily for health care professionals caring
CHB
• Assist policy makers in optimizing care

5. AASLD formulated a list of discrete questions
that physicians are faced with in daily practice

6. Whom to be treat???
• 1. Should adults with immune active CHB
be treated with antiviral therapy?
• 2. Should adults with immune-tolerant
infection be treated with antiviral
therapy ?

7. How long should treat????
• 3. Should antiviral therapy be
DISCONTINUED in (HBeAg)-positive
persons who developed HBeAg
seroconversion on therapy?

8. How long should treat????
• 4. Should antiviral therapy be
DISCONTINUED in persons with HBeAg-
negative infection with sustained HBV
DNA suppression on therapy?

9. ENTECAVIR OR TENOFOVIR??
• 5. Does entecavir when compared to
tenofovir therapy have a different
impact on renal & bone health?

10. Inadequate response???
• 6. Is there any benefit of adding second
antiviral agent in persons with
persistent low levels of viremia treating
with either tenofovir or entecavir?

11. In compensated cirrhosis???
• 7. Should persons with compensated
cirrhosis & low levels of viremia be
treated with antiviral agents?

12. Pregnancy & children
• 8. Should HBsAg positive pregnant
women with high viral load receive
treatment in third trimester to prevent
perinatal transmission of HBV?
• 9. Should children with HBeAg-positive
CHB to be treated with antiviral therapy
?

13. BACKGROUND
• Globally 240 million persons have CHB,highest
in Africa and Asia.
• deaths from cirrhosis & HCC were estimated at
310,000 and 340,000 per year, respectively

14. To reduce morbidity & mortality
• identify infected individuals through targeted
screening
• prevent new infections through vaccination
• monitor &treat those at risk for complications
& surveillance for HCC

16. NATURAL HISTORY
• Four phases
• Serial monitoring of HBV DNA & ALT levels is
important to characterize phase of infection.
• Dilemma of “gray zones,”

17. IMMUNE
TOLERANT
IMMUNE
ACTIVE
INACTIVE CHB REACTIVATION

18. Immune tolerant phase
• highly replicative/ low inflammatory phase.
• HBV DNA levels elevated
• ALT levels normal (<19 U/L for females & <30 U/L
for males)
• Biopsy - no inflammation or fibrosis.
• highly variable duration, but longest in those
infected perinatally.

19. Immune active phase
• Elevated ALT &HBV DNA & liver injury.
• transition from HBeAgpositive immune-active
to inactive phase - HBeAg seroconversion.
• Rate of spontaneous seroconversion
children - <3%
puberty - 8%
adults - 12% per year.

20. Inactive CHB phase
• HBV DNA levels are low /undetectable,
• ALT levels normal & anti-HBe is present
• Liver histology - minimal necroinflammation,
but variable fibrosis
• 67%-80% will remain in inactive CHB phase.

21. HBeAg-negative immune reactivation
phase
• 10%20% show reactivation of HBV replication
• liver histology - necroinflammation & fibrosis
• HBV variants in precore or core promoter
region

22. PHASE ALT HBV DNA HBeAg Liver
histology
Immune
Tolerant
Normal >1
millionIU/ML
positive Minimal
inflammation
Immune
Active
Elevated >20,000IU/
ML
positive Moderate to
severe
Inactive
CHB
Normal Low or
undetectable
negative Minimal
necro -
inflammation
Immune
reactivation
elevated elevated negative Moderate to
severe

25. Male sex
• >40 yrs age
• immunocompromised
High serum HBV DNA
• Prolonged time to Hbeg seroconversion
• Elevated ALT levels
• Genotype C
• Development of HBeAg-negative CHB
Concurrent viral infections (HCV, HIV, and HDV)
• Heavy alcohol use
• Metabolic syndrome (obesity, diabetes)
RISK FACTORS FOR DEVELOPMENT OF CIRRHOSIS & HCC

26. DIAGNOSIS & STAGING OF CHB
history and physical examination
• Symptoms/signs of cirrhosis
• Risk factors for coinfection, alcohol
• Family history of HBV infection & liver cancer
• Vaccination status

27. Routine lab tests
• CBC
• LFT
• Albumin
• INR
Viral serology
• Markers of HBVreplication
• Tests for coinfection HCV & HIV

28. Imaging/staging studies
• Abdominal USG
• Vibration-controlled transient elastography
• Serum fibrosis panel(APRI,FIB-4,orFIbroTest)
• Liver biopsy

29. SERUM MARKERS OF FIBROSIS

30. SERUM MARKERS OF FIBROSIS
Score <1.45 -90% npv
for fibrosis
Score >3.25-65% ppv
for fibrosis

31. SERUM MARKERS OF FIBROSIS

32. ANTI VIRAL THERAPY
• to decrease morbidity & mortality related to CHB
 Sustained suppression of HBV replication;
• normalization of serum ALT
• loss of HBeAg with or without detection of anti-Hbe
• improvement in liver histology
• Immunological cure - HBsAg loss & sustained
HBV DNA suppression

33. DRUG ADULT DOSAGE USE IN CHILDREN
Peg-IFN-2a(adult)
IFN-a-2b (children
180 microgram weekly >1 year Dose: 6 million
IU/m2 TIW‡
Lamivudine 100 mg daily >2 years Dose: 3 mg/kg
daily to max 100 mg
Telbivudine 600 mg daily -
Entecavir 0.5 or 1.0 mg daily >2 years Dose: weight-
based to 1030 kg; above
30 kg 0.5 mg daily
Adefovir 10 mg daily >12 years 10 mg daily
Tenofovir 300 mg daily 12 years 300 mg daily

34. Drug Pregnancy
cat
Potential
side effects
monitoring
Peg-IFN-2a(adult) IFN-a-
2b (children
C Flu-like
symptoms,
fatigue, mood
disturbances,
cytopenias,
autoimmune
disorders in
adults Anorexia
&weight loss in
children
CBCmonthly to every 3 months)
TSH (every 3 months)
Clinical monitoring for
autoimmune, ischemic,
neuropsychiatric & infectious
complications
Lamivudine C Pancreatitis
Lactic
acidosis
Amylase
Lactic acid levels
Telbivudine B Creatine kinase
elevations &
myopathy
Peripheral
neuropathy
Lactic acidosis
Creatine kinase
Lactic acid levels
Entecavir C Lactic Lactate levels

35. Adefovir C Acute renal
failure
Fanconi
syndrome
Nephrogenic
diabetes
insipidus
Lactic acidosis
•Creatinine clearance,if at
risk for renal impairment,
•Creatinine clearance, serum
phosphate, urine glucose,
and protein at least annually
Bone density study at
baseline &during treatment
in persons with history of
fracture or risks for
osteopenia
Lactic acid levels
Tenofovir B Nephropathy
Fanconi
syndrome
Osteomalacia
Lactic acidosis
•Creatinine clearance.
• serum phosphate, urine
glucose&protein annually
•Bone density study at
baseline &during treatment
in persons with history of
fracture or risks for
osteopenia
•Lactic acid levels

36. Treatment of Persons With Immune-
Active CHB
• START ANTIVIRAL THERAPY for adults
with immune-active CHB (HBeAg negative /
HBeAg positive) to decrease liver-related
complications
Quality/Certainty of Evidence: Moderate
Strength of Recommendation: Strong

37. • Peg-IFN, entecavir, or tenofovir preferred
initial therapy for adults with immune-active
CHB.
Quality/Certainly of Evidence: Low
Strength of Recommendation: Strong

38. Decision to treat persons with immune-active
CHB but ALT <2 ULN & HBV DNA below
thresholds are:
• Age: Older age (>40 years)
• Family history of HCC
• Previous treatment history
• Presence of extrahepatic
manifestations: Indication for treatment
independent of liver disease severity

39. Patient-specific factors that need to be
considered in choosing between PegIFN,
entecavir, & tenofovir
.
• Desire for finite therapy
• Anticipated tolerability of treatment side
effects .
• Comorbidities
• Previous history of lamivudine resistance
• Family planning
• HBV genotype
• Medication costs.

40.  Duration of NA-based therapy is variable
HBeAg status
duration of HBV DNA suppression
 presence of cirrhosis/decompensation.
• All NAs - dose adjustment in persons
creatinine clearance <50 mL/min.
• Staging of disease using noninvasive
methods or liver biopsy is useful in guiding
duration of therapy.
• Antiviral therapy - not eliminate risk of HCC
& HCC surviellance should continue .

41. Treatment of Adults With Immune-
Tolerant CHB
• NO antiviral therapy for adults with immune-
tolerant CHB
. Quality/Certainly of Evidence: Moderate
Strength of Recommendation: Strong

42.  ALT levels - tested every 6 months for
adults with immunetolerant CHB
 to monitor for potential transition to
immune-active / -inactive CHB.
 Moderate-to-severe necroinflammation
/ fibrosis on liver biopsy
 start antiviral therapy, if other causes of
liver disease excluded.

43. Treatment of HBeAg Positive
Immune-Active Chronic Hepatitis
Persons Who Seroconvert to Anti-HBe
on NA Therapy
• DISCONTINUE NAs after a period of
treatment consolidation
Quality/Certainty of Evidence: Very Low
Strength of Recommendation: Conditional

44. • Period of consolidation therapy - treat for
at least 12 months of persistently normal ALT
levels & undetectable serum HBV DNA levels.
• Not known whether longer duration of
consolidation would further reduce rates of
virological relapse.
• Alternative approach -treat until HBsAg loss.

45. Decisions on treatment duration & length of
consolidation before treatment discontinuation
require careful consideration of :
• (i) risk for virological relapse, hepatic
decompensation, HCC & death
• (ii) burden of continued antiviral therapy,
financial concerns , adherence & potential for
drug resistance
• (iii) patient & provider preferences.

46. HBeAg-positive adults with cirrhosis
• INDEFINITE ANTIVIRAL THERAPY -
HBeAg-positive adults with cirrhosis with CHB
who seroconvert to anti-HBe on NA therapy,
unless there is strong rationale for treatment
discontinuation.
Quality/Certainty of Evidence: very Low
Strength of Recommendation: Conditional

47. Duration of Treatment in Persons
With HBeAg-Negative Immune-Active
CHB
• INDEFINITE ANTIVIRAL THERAPY -
HBeAg-negative immune-active CHB, unless
there is a competing rationale for treatment
discontinuation.
Quality/Certainly of Evidence: Low
Strength of Recommendation: Conditional,

48. A decision to discontinue therapy for
HBeAgnegative adults without cirrhosis requires
consideration of :
• (i) risk for virological relapse, hepatic
decompensation, hcc & death
• (ii) burden of antiviral therapy, financial
concerns , adherence & drug resistance
• (iii) patient & provider preferences.

49. Persons who stop antiviral therapy should
monitored every 3 months for at least 1 year for:
• recurrent viremia,
• ALT flares,
• Seroreversion
• clinical decompensation

50. INACTIVE CHRONIC HEPATITIS B
Antiviral therapy NOT recommended
Persons without cirrhosis
 HBeAg negative
 normal ALT
 low-level viremia (<2,000 U/mL).

51. Renal and Bone Disease in Persons on
NA Therapy
• NO PREFERENCE between entecavir and
tenofovir regarding potential long-term risks of
renal and bone complications.
Quality/Certainly of Evidence: Very Low (bone); Low (renal)
Strength of Recommendation:

52. • NO significant differences in renal dysfunction,
hypophosphatemia, or bone mineral density
between HBV-infected persons treated with
tenofovir or entecavir.
• In persons on tenofovir - serum creatinine,
phosphorus, urine glucose & urine protein
should be assessed before treatment initiation &
periodically

53. In tenofovir-associated renal dysfunction
and/or osteoporosis/osteomalacia.
 Tenofovir should be discontinued & substitute
with alternate NA with consideration for
previous drug resistance.
• Dosage of NAs should adjusted based on renal
function & creatinine clearance.

54. Management of Persons With
Persistent Low-Level Viremia on NA
Therapy
• Persons with persistent low-level viremia
(<2,000 IU/mL) on entecavir / tenofovir
monotherapy - continue monotherapy,
regardless of ALT.
Quality/Certainty of Evidence: Very Low
Strength of Recommendation: Conditional

55. • Persistent viremia - defined as detectable HBV
DNA after 48 weeks of treatment.
• With current preferred therapies of entecavir
and tenofovir, persistent viremia defined as
plateau in decline of HBV DNA and/or failure to
achieve undetectable HBV DNA level after 96
weeks of therapy.
• NO evidence for adding a second drug or
switching to another drug continuing
monotherapy.

56. Strategies in virological breakthrough on
entecavir or tenofovir monotherapy:
either switch to another antiviral monotherapy
with high barrier to resistance / add second
antiviral drug that lacks crossresistance
Quality/Certainty of Evidence: Very Low
Strength of Recommendation: Conditional

57. • Viral breakthrough - increase in HBV DNA by >1
log compared to nadir or HBV DNA 100 IU/mL in
persons on NA therapy previously undetectable
levels (<10 IU/mL).
• Confirmatory testing should obtained . Resistance
testing assist decisions regarding subsequent
therapy.
• A confirmed virological breakthrough-
 switch to other antiviral monotherapy with high
genetic barrier to resistance
 add second antiviral with complementary
resistance profile .

58. Frequency of HBV DNA monitoring
• Every 3 months until HBV DNA undetectable
• Then every 3-6 months - for detection of
persistent viremia & virological breakthrough.

59. Management of Adults With Cirrhosis
and Low-Level Viremia
• Compensated cirrhosis &low levels of
viremia (<2,000 IU/ mL) - treat with antiviral
therapy to reduce the risk of decompensation,
regardless of ALT level.
Quality/Certainly of Evidence: Very Low
Strength of Recommendation: Conditional

60. • HBsAg-positive adults with
decompensated cirrhosis – treat with
antiviral therapy indefinitely regardless of
HBV DNA level, HBeAg status, or ALT level
Quality/Certainly of Evidence: Moderate
Strength of Recommendation: Strong

61. • Entecavir & tenofovir are preferred drugs
• Peg-IFN contraindicated in persons with
decompensated cirrhosis
• Concurrent consideration for liver transplantation
indicated in eligible persons.

62. • Lactic acidosis reported with some NAs
 Persons with advanced decompensated cirrhosis
at higher risk.
 Follow-up of laboratory & clinical status
necessary.
• Treatment with antivirals not eliminate risk of
HCC
• HCC surveillance must

63. Treatment of CHB in Pregnancy
• ANTIVIRAL THERAPY to reduce the risk of
perinatal transmission of hepatitis B in HBsAg-
positive pregnant women with HBV DNA level
>200,000 IU/mL.
Quality/Certainty of Evidence: Low
Strength of Recommendation: Conditional

64. • The infants of all HBsAg-positive women should
receive immunoprophylaxis
• Only antivirals studied in pregnant women-
lamivudine, telbivudine & tenofovir.
• Limited data on level of HBV DNA - antiviral
therapy is recommended.
• The level of >200,000 IU/mL (1 million copies/
mL) is conservative recommendation

65. • Antiviral therapy started at 28-32 weeks of
gestation
• Antiviral therapy discontinue at birth to 3
months postpartum
• . With discontinuation of treatment, women
should be monitored for ALT flares every 3
months for 6 months.

66. • For pregnant women with immune-active
hepatitis B, treatment should be based on
recommendations for nonpregnant women.
• Breastfeeding not contraindicated.
• C-section not indicated

67. • NO ANTIVIRAL THERAPY -HBsAg-
positive pregnant woman with HBV DNA
<200,000 IU/mL.
Quality/Certainty of Evidence: Low
Strength of Recommendation: Strong

68. Treatment of CHB in Children
• START ANTIVIRAL THERAPY -
HBeAgpositive children (ages 2 to <18 years)
with both elevated ALT & measurable HBV DNA
levels.
Quality/Certainty of Evidence: Moderate
Strength of Recommendation: Conditional

69. • Interferon-α-2b > children 1 year
• lamivudine & entecavir > children 2 years
• Peg-IFN α-2a NOT approved for children with
CHB
• Treatment with entecavir associated with lower
viral resistance compared to lamivudine.
• Tenofovir > children 12 years

70. SUMMARY OF RECOMMENDATIONS
IMMUNE TOLERANT CHB
Anti viral therapy NOT recommended
Monitor ALT every 6 months

71. SUMMARY OF RECOMMENDATIONS
IMMUNE ACTIVE PHASE
ANTIVIRAL THERAPY RECOMMENDED
PEG IFN,ENTECAVIR OR TENOFOVIR PREFFERED AGENTS

72. SUMMARY OF RECOMMENDATIONS
Hbeg + immune active CHB
cirrhosis
Discontiue tx after Indefinite antiviral therapy
consolidation
therapy

73. SUMMARY OF RECOMMENDATIONS
HBeAg negative immune active CHB
TREAT INDEFINITELY

74. SUMMARY OF RECOMMENDATIONS
• No prefernce between entecavir & tenofovir
regarding renal & bone complications
• Compensated cirrhosis with low level of
viremia - treat to reduce decompensation
• Decompensated cirrhosis treat indefinitely