1. Progression of chronic Hepatitis B From beginning to end
Dr Maggie Ow
Gastroenterologist, ADHB

2. Disclaimer Please note:
The presentations express the views and opinions of the presenter which are based on the latest information and data available at the time of preparation and are not necessarily endorsed by Gilead.
Any patient cases and treatment options referred to are in the context of contemporary knowledge and medical practice in the field.

3. Hepatitis B (HBV) progression

4. Factors influencing natural history of HBV
Croagh C, et al. World J Gastro

5. Trépo C, et al. Lancet

6. Development of liver fibrosis

7. Immune tolerant phase

8. Immune tolerant phase Young, HBeAg+, normal ALT, very high HBV DNA
Seen in patients with perinatal/horizontal transmission
Can last for several decades (perinatal longer than horizontal)
Chu CM, et al. Clin Infect Dis (top)
Hadziyannis SJ. J Hepatol (bottom)

9. Very little progression
However, fibrosis can still occur, especially in older patients (>40)
Need to watch ALT closely
High-normal/transient or minimal elevation
Hui CK, et al. Hepatology (left)
Lai M, et al. J Hepatol (right)

10. Immune clearance phase

11. Immune clearance phase: HBeAg positive chronic hepatitis
HBeAg+ Persistent/intermittent elevation of ALT High HBV DNA (not as high as immune tolerant) Flares Active inflammation in liver driven by immune response

12. Patterns of ALT abnormality in immune clearance phase
Flares
Transient/mild ALT elevation
No strict definition:
ALT >5x ULN or >300 IU/mL
More common in men
Risk (~5%) of hepatic decompensation
May be predicted by HBV DNA > 8 logs IU/mL
Rarely can be fatal
Persistent or intermittent low- level inflammation over time Carries risk of progressive fibrosis/cirrhosis and HCC

13. HBeAg seroconversion
Higher chance of HBeAg seroconversion with higher ALT and increasing time
With flare: 46.4% chance within 3 months
Other factors – AFP >100, bridging necrosis on biopsy
Yuen MF, et al. Gut

14. HBeAg seroconversion – summary of factors that impact on timing
Age of patient (average age in the 30s)
Increasing age i.e. time
High ALT
Age at acquisition of virus (perinatal later than horizontal)
HBV genotypes
e.g. Genotype B earlier than genotype C

15. HBeAg status and cirrhosis
Outcome of HBeAg seroconversion: transition to immune control phase i.e. inactive carrier
HBeAg status and cirrhosis
HBeAg status and HCC
Liaw YF. Hepatol Int
Yang HI, et al. NEJM

16. Immune control phase

17. Immune control phase – the inactive carrier
HBeAg- and anti-HBe+
ALT persistently normal (for at least 1 year)
HBV DNA very low
Ideal cut-off to define this phase has not been determined, but taken as:
<2000 IU/mL (although accepting some inactive carriers can have HBV DNA greater than 2000 but below 20,000 IU/mL)
Usually indicates favourable long-term outcome

18. Long-term outcome of HBeAg-negative patients with persistently normal ALT
Tai DI, et al. Hepatology

20. NO…. There’s more!
Relapse of hepatitis may occur due to HBeAg seroreversion or development of HBeAg negative chronic hepatitis Occur in up to one-third of seroconverters Risk decreases with time
Chu CM, et al. Hepatol Int

21. Reactivation phase

22. HBeAg-negative chronic hepatitis
May follow seroconversion or develop after years/decades of inactive carrier state Risk higher in males, genotype C, HBeAg seroconversion >40 years old Mutation in precore or basal core promoter region Fluctuating ALT and HBV DNA Low rates of prolonged spontaneous remission High risk of progressive disease

23. HBV DNA

24. REVEAL-HBV study
Taiwanese community cohort 3653 patients with chronic HBV 85% HBeAg- Mean follow up 11 years

25. HBV DNA >2000 IU/mL is associated with increased risk of cirrhosis and HCC
HBV DNA and cirrhosis
HBV DNA and HCC
Iloeje UH, et al. Gastroenterology
Chen CJ, et al. JAMA

26. Mortality correlates strongly with HBV DNA
HBV DNA and all-cause mortality
HBV DNA and liver-related mortality
Iloeje UH, et al. Gastroenterology

27. HBsAg

28. ERADICATE-B
Taiwanese hospital cohort 2688 patients with chronic HBV 80% HBeAg- Mean follow up 14 years

29. HBsAg >1000 IU/mL is associated with increased risk of cirrhosis and HCC in patients with low level viraemia (HBV <2000 IU/mL)
HBsAg and cirrhosis
HBsAg and HCC
Tseng TC, et al. Hepatology
Tseng TC, et al. Gastroenterology

30. ALT

31. Level of ALT associated with risk of cirrhosis and HCC
ALT and cirrhosis
ALT and HCC
Wong GL, et al. Am. J. Gastroenterol
Chen CF, et al. Gastroenterology

32. HBsAg-negative phase

33. HBsAg-negative phase Spontaneous HBsAg clearance
Closest endpoint to a “cure”
Remembering that HBV is archived in the host genome in the form of cccDNA
Annual rate ~ %
Increases with time – cumulative rate of 8% at 10 years, 25% at 20 years, and 45% at 25 years of follow up
Excellent prognosis in the majority
HCC may still occur (albeit at a very low rate), especially if cirrhosis present

34. Low HBV DNA (<300 copies/mL) is an important determinant of eventual HBsAg loss
Liu J, et al. Gastroenterology

35. SEARCH-B
Taiwanese hospital cohort 390 patients with chronic HBV Spontaneous HBeAg seroconverters Mean follow up 7 years

36. Low level of HBsAg (<100 IU/mL) predicts eventual HBsAg loss independent of HBV DNA
All patients
HBV DNA <200 IU/mL
Tseng TC, et al. Gastroenterology

37. Summary

38. In summary:
In chronic HBV, there is a long period of immune tolerance whereby very little inflammatory activity occurs.
Regular interval monitoring of ALT and HBV DNA are important to detect patients with active chronic hepatitis:
Onset of the immune clearance phase (HBeAg+ chronic hepatitis)
Relapse of hepatitis after HBeAg seroconversion (HBeAg- chronic hepatitis)

39. Sustained inactive carrier state has a good prognosis
HBeAg seroconversion
Timing depends on age, ALT, mode of acquisition, and genotype
Sustained inactive carrier state has a good prognosis
Relapse of hepatitis on the other hand is associated with progressive disease
Higher risk of relapse in men, genotype C, older age of seroconversion
HBV DNA, ALT, and HBsAg level are all independent predictors of progression to cirrhosis and HCC
HBV DNA >2000 IU/mL
HBsAg > 1000 IU/mL in those with low viral load
Elevated ALT, including:
“high normal” in a patient >40
minor elevations <2x ULN
transient elevations
HBsAg seroclearance is the closest to a “cure”
Low/undetectable HBV DNA and low level HBsAg <100 IU/mL are important determinants