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

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.

Hepatitis B (HBV) progression

Factors influencing natural history of HBV Croagh C, et al. World J Gastro. 2014.

Trépo C, et al. Lancet. 2014.

Development of liver fibrosis

Immune tolerant phase

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. 1993. (top) Hadziyannis SJ. J Hepatol. 2011. (bottom)

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. 2007. (left) Lai M, et al. J Hepatol. 2007. (right)

Immune clearance phase

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

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

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. 2003.

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

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. 2009. Yang HI, et al. NEJM. 2002.

Immune control phase

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

Long-term outcome of HBeAg-negative patients with persistently normal ALT Tai DI, et al. Hepatology. 2009.

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. 2007.

Reactivation phase

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

HBV DNA

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

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. 2006. Chen CJ, et al. JAMA. 2006.

Mortality correlates strongly with HBV DNA HBV DNA and all-cause mortality HBV DNA and liver-related mortality Iloeje UH, et al. Gastroenterology. 2007.

HBsAg

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

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. 2013. Tseng TC, et al. Gastroenterology. 2012.

ALT

Level of ALT associated with risk of cirrhosis and HCC ALT and cirrhosis ALT and HCC Wong GL, et al. Am. J. Gastroenterol. 2008. Chen CF, et al. Gastroenterology. 2011.

HBsAg-negative phase

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 ~0.5-2.0% 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

Low HBV DNA (<300 copies/mL) is an important determinant of eventual HBsAg loss Liu J, et al. Gastroenterology. 2010.

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

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. 2011.

Summary

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)

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