Hepatitis B management, all that you should know

1. Hepatitis B management
DR. NIKHIL CHANDRA ROY

2. 400 million with CHB
Prevalence of HBV: Global Estimates

3. HBV in Bangladesh
• Intermediate prevalence (5%) region.
• HBV is responsible for
• 31.25% cases of acute hepatitis
• 76.3% cases of chronic hepatitis
• 61.3% cases of cirrhosis of liver
• 33% cases of HCC in Bangladesh
• 48.7% of CHB patients are HBeAg positive, 51.3% are HBeAg negative
Ref. guideline for treating hepatitis B virus infection in Bangladesh

4. Assessment of persons with chronic HBV infection
• History
• Previous jaundice
• Mode of HBV acquisition:
• Family history of HBV and HCC
• Comorbidities: obesity, DM, Fatty liver
• Physical examination
• Features decompensation
Ref.Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, p-17

5. Lab Investigations
• HBV Serology:
HBeAg, anti-Hbe
HBV DNA
• Viral co-infection: Antibody to HCV, HDV, HIV
• Biochemical tests:
 ALT, AST, ALP, Serum albumin, bilirubin
 Prothrombin time(PT)
• Hepatic ultrasound
• AFP(for HCC) and Endoscopy for varices in persons with cirrhosis
• Baseline renal function: serum creatinine levels ,eGFR
Ref.Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, p-17

6. • Liver biopsy is needed to determine the stage of fibrosis and/or the
grade of activity in patients with a high viral load and high-normal or
minimally raised ALT levels
• Noninvasive tests alternative to liver biopsy
 Biochemical parameters
AST/ALT ratio
Fibrosis score-4 (FIB-4)
 AST to platelet ratio index (APRI)
 Fibrotest
 Fibroscan
Ref.Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, p-17

7. HBV: Important terminology
• HBeAg seroconversion: Loss of HBeAg and detection of anti-HBe in a person
who was previously HBeAg positive and anti-HBe negative
• Hepatic decompensation: Defined as significant liver dysfunction as indicated by
raised serum bilirubin (more than 2.5 times the upper limit of normal) and prolonged
prothrombin time (prolonged by more than 3 s), or INR>1.5 or occurrence of
complications such as ascites and hepatic encephalopathy(APSL)Or
Clinical complications of cirrhosis become manifest, including jaundice, ascites,
spontaneous bacterial peritonitis, oesophageal varices and bleeding, hepatic
encephalopathy, sepsis and renal failure
Ref. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, P-5-6
WHO Guidelines For The Prevention, Care And Treatment Of Persons With Chronic Hepatitis B Infection , March 2015, XV

8. HBV: Important terminology
• Viral relapse: Serum HBV DNA > 2000 IU/ml after stopping treatment in patients
with virological response
• Clinical relapse: Viral relapse along with ALT >2X ALT
• Sustained off-treatment virological response: No clinical relapse during follow-
up after stopping therapy
• HBsAg seroconversion: Loss of HBsAg and development of anti-HBs
• Virological response: Undetectable serum HBV DNA during therapy
Ref. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, P-5-6

9. HBV: Important terminology
• Virological breakthrough: Increase of serum HBV DNA >1 log10 IU/ml (10 fold)
from nadir after initial virological response during therapy, as confirmed 1 month
later
• Primary antiviral treatment failure: may be defined as failure of an antiviral
drug to reduce HBV DNA levels by ≥1 x log10 IU/mL within 3 months of initiating
therapy
• Secondary Antiviral treatment failure: Viral breakthrough in an adherent
patient (due to drug resistance)
• Cross resistance: Mutation selected by one antiviral agent that also confers
resistance to other antiviral agents
Ref. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, P-5-6
WHO Guidelines For The Prevention, Care And Treatment Of Persons With Chronic Hepatitis B Infection , March 2015, XV

10. GUIDELINES

11. Goal of therapy
To prevent progression of
disease to cirrhosis, end-
stage liver disease, HCC,
death
To improve
survival and
quality of life
Prevention of
transmission of
HBV to others

12. Indications of therapy in CHB infection
Compensated cirrhosis
HBV DNA >
2000IU/ML@
YES TREAT
YESALT> 2 X ULN* TREAT
* Other causes of ALT elevation should be excluded
Ref. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance, p-1588
@ Regardless of ALT Level

13. Indications of therapy in CHB infection
Decompensated cirrhosis
Ref. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance, p-1588-1589
YES
• Antiviral therapy regardless of HBV DNA
level, HBeAg Status, or ALT level
• Concurrent consideration for LT in
eligible persons
• Close monitor for AE of antiviral drugs
e.g. renal insufficiency, lactic acidosis
Decompensated cirrhosis

14. Indications of therapy in CHB infection
without cirrhosis
• HBeAg positive CHB
• HBeAg negative CHB

15. Ref. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance, P-1571, FIG. 1.

16. Ref. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance, P-1571, FIG. 1

17. Treatment strategies
InterferonNucleos(t)ide analogues
Combined antiviral and
immunomodulatory effectDirect antiviral effect
• Conventional IFN-α
• Peg-IFN α
Low barrier against HBV resistance
• Lamivudine(LAM)
• Adefovir(ADV)
• Telbivudine(TBV)
High barrier to HBV resistance
• Entecavir(ETV)
• Tenofovir(TDF, TAF)
Currently, there are two main treatment options for CHB patients:

18. Comparison of two treatment strategies for chronic hepatitis B
Features Pegylated interferon Nucleos(t)ide analogues
Strategy Induction of a long-term immune
control
Stopping hepatitis and disease progression by
inhibiting viral replication
Goal Low HBV DNA level (<2000 IU/ml) and
normal ALT Level
Undetectable HBV DNA level and normal ALT level
Level of viral
suppression
Moderate (variable response pattern) Universally high
Effect on HBeAg loss Moderate, depending on baseline
characteristics
Low in the first year, increases to moderate during
long-term treatment
Effect on HBsAg levels Variable, depending on baseline
characteristics (higher as compared to
NA)
Low: slowly increases with treatment time in HBeAg+
patients; usually very low in HBeAg(-)patients
Duration Finite(48 weeks) Prolonged or indefinite
Contraindications Many (i.e., decompensated disease,
pregnancy, co-morbidities etc.)
None
Tolerability Low High
Ref. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection, p-377

19. Choice of agent
• Oral agents :
• NA antiviral agents are mainstay of therapy.
• High barrier to drug resistance (tenofovir or entecavir) are preferred as 1st -
line drugs.
• Low barrier to resistance (lamivudine, adefovir or telbivudine) are not
recommended unless 1st- line drugs are not available or appropriate.
Interferon:
• The best candidates for interferon higher ALT levels(>2X ULN), lower HBV
DNA levels; and genotype A.
• 30% HBeAg loss in short term treatment
• Lower response rate are lower in HbeAg negative patients
• severe side effects , parenteral administration, costly drug.
Ref. Davidson principle and practice of medicine, 22th ed, P-876, APSL

20. Recommended drugs for the treatment of CHB and their
doses in adults
Drug Dose
Tenofovir dipovoxil fumerate (TDF) 300 mg once daily
Tenofovir alafenamide (TAF) 25 mg daily
Entecavir* 0.5 mg once daily
* For decompensated cirrhosis 1 mg once daily

21. Drug Dose
Telbivudine 600 mg once daily
Lamivudine 300 mg once daily
Adefovir 10 mg once daily
Pegylated interferon alpha-2a 180 µg once per week
Pegylated interferon alpha-2b 0.5 or 1.0 µg per kg per week
 Pregnancy category B: TDF, Telbivudine

22. When can treatment be stopped?
• IFN: Defined duration, 12 months for both HBeAg+ and HBeAg- patients
• Neucleos(t)ide analogue until treatment endpoint
• HBeAg + patients HbeAg seroconversion + 1 year consolidation rx
• HbeAg – patients endpoint not defined , HbsAg loss 5% after 5 years
• Cirrhotics life long treatment.

23. Endpoint of therapy
Sustained off-therapy
HBsAg loss
Maintained virological
remission
(undetectable HBVDNA)
Sustained off-therapy
virological response
• The ideal endpoint
• with or without
seroconversion to
anti-HBs
• Infrequently
achievable
• HBV DNA < 2000
IU/ml
• ALT <2X ALT
• in both HBeAg-
positive (with
sustained anti-HBe
seroconversion) and
HBeAg-negative
patients
• in HBeAg + patients
not achieving anti-
HBe seroconversion
under long-term
therapy
• in HBeAg-negative
patients is the next
most desirable
endpoint.
Ref. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update,

24. Endpoint of antiviral therapy
Non-cirrhotic HBeAg positive CHB
Antiviral therapy
Variable treatment duration
At least 1 year of
consolidation therapy*
STOP
HBV DNA
undetectable
ALT
Normal
HBeAg
Seroconversion
* Preferably 3 years of additional therapy ac. to Asian-Pacific clinical
practice guidelines on the management of hepatitis B: a 2015 update p-32

25. Endpoint of antiviral therapy
Non-cirrhotic HBeAg negative CHB
Antiviral therapy
Llong term/ indefinite treatment STOP
HBV DNA
undetectable
ALT
Normal
HBsAg
loss
NAs should be discontinued after confirmed HBsAg loss with or without
anti-HBs seroconversion, however it is relatively infrequent
Discontinuation of NAs who have achieved long term (≥3 years) virological
suppression may be considered if close post-NA monitoring can be guaranteed
,EASL P-379

26. HCC screening guideline in HBsAg patients
• All patients with HBV-related cirrhosis
• High risk group
• Asian or black men > 40 years and Asian women over 50 years
• First degree family members with HCC
• Coinfection with HCV, HDV or HIV infection
• With fatty liver
• Modalities and frequency: USG with or without AFP every 6 months
Ref. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance, P-1574

27. Management of coinfection with HCV
Ref. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, p-56
*
* For 24-48 weeks , depending on HCV genotype

28. Hepatitis B treatment during pregnancy
• All pregnant women should be screened for HBsAg.
• without advanced fibrosis who plans a pregnancy in the near future, it may be prudent to
delay therapy until the child is born
• Pregnant women with CHB and advanced fibrosis or cirrhosis, therapy with TDF is
recommended
• If already on NA therapy, TDF should be continued while ETV or other NA should be switched
to TDF
• In all pregnant women with high HBV DNA levels (>200,000 IU/ml)levels antiviral prophylaxis
with TDF , at week 24–28 of gestation and continue for up to 3 months after delivery
• Active and passive immunization of newborn (<12h)
• Breast feeding is not contraindicated in HBsAg-positive untreated women or on TDF-based
treatment or prophylaxis
EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus
infection, p-389
Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance, p-
1564,1589

29. Treatment of Acute Hepatitis B
• > 95% recover spontaneously in immunocompetent adults
• Indication of Rx
• acute liver failure or
• Protracted, severe course, as indicated by total bilirubin >3 mg/dl (or direct
bilirubin >1.5 mg/dL), international normalized ratio >1.5, encephalopathy, or
ascites
• Drug of choice: ETV, TDF or TAF, Peg-IFN is contraindicated.
• Treatment should be continued until HBsAg clearance is confirmed or
indefinitely in those who undergo liver transplantation.
Ref. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance, p-1579

30. Management of treatment failure on NA therapy
• To prevent emergence of resistance, NAs with the high potency and high barrier to
resistance (entecavir and tenofovir) should be administered and adherence
reinforced .
• In the compliant patient, testing for genotypic resistance should be performed .
• Entecavir should not be used in patients with prior lamivudine or telbivudine
resistance, because the risk of subsequent entecavir resistance is high
Antiviral Resistance by Genotypic Testing Switch Strategy
lamivudine, adefovir, or entecavir-resistance Tenofovir (TDF or TAF)
Tenofovir resistance (very rare)
Adefovir resistance
Entecavir
Multidrug resistant Tenofovir plus Entecavir or tenofovir monotherapy
Ref. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance,P-1580

31. Treatment of
liver transplant recipients with hepatitis B
• All HBsAg-positive patients undergoing liver transplantation should receive
prophylactic therapy with NAs with or without HBIG post-transplantation
regardless of HBeAg status or HBV-DNA level pretransplant.
• Entecavir, TDF, and TAF are preferred antiviral drugs because of their low
rate of resistance with long-term use.
• Addition of HBIG varies according to patients risk group .
Ref. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, P-53, AASLD , P-1582

32. Ref. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, P-54, AASLD, P-1582-83
Or HBIG only for 5 to 7 days

33. Treatment in patients with CKD, on dialysis and renal
transplant patients
• NAs (entecavir or telbivudine) represent the first-line treatment options for
chronic HBV-infected patients with any level of renal dysfunction and renal
replacement therapy. NAs should be dose adjusted based on creatinine
clearance rates
• Peg-IFN should be avoided in renal transplant patients because of the risk
of rejection
Ref. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, P-62

34. THANK YOU