Quantification of serum HBs-Ag: is it useful?

Dr. Mohamed A MekkyLecturer of Tropical Medicine and Gastroenterology

• CHB infection is a global health problem affecting more than 350 million people worldwide.

• Prolonged liver inflammation caused by active infection with the hepatitis B virus (HBV) may result in progression to liver fibrosis, cirrhosis and ultimately HCC and death

Chronic HBV infection

Chronic hepatitis B

Compensated cirrhosis

Decompensated cirrhosis

Hepatocellular Carcinoma

Death

Inactive carrier state

2-6% for HBeAg(+) hepatitis B8-10% for HBeAg(-) hepatitis B

<1.0%

2-3%

7-8%

20-50%20-50%

<0.2%

Annual rates of progression during chronic HBV infection

Fattovich et al. 2004.

3-5%

60-70%30-40%

Undetectability of HBV-DNA does not mean absence clearance of

viral infection

But, at the moment we are missing markers identifying

the achievement of an effective HBV infection control

HBS-AG

• HBsAg derives mainly from the intrahepatic viral mini-chromosome

• serum levels of HBsAg reflect the complex interplay between virus and immune system

• qHBsAg levels vary during the different phases of chronic HBV infection.

qHBs-Ag Natural History

HCC risk

Treatment response

Viral clearance

qHBs-Ag & NATURAL HISTORY

• HBsAg serum levels decline progressively from the immune-tolerant to the low replicative phase

• Studies have reported higher and more stable HBsAg levels in immune-tolerant carriers, higher than those observed in immune clearance phase.

qHBs-Ag & clearance • HBsAg level <100 IU/ml at 1 year post-HBeAg

seroconversion can predict HBsAg loss within 6 years• HBsAg <10 IU/ml is the strongest predictor of HBsAg loss

in HBeAg-negative patients who have HBV DNA <2000 IU/ml

• Decreasing HBsAg level can predict HBsAg seroclearance in inactive CHB patients

Tseng, Kao et al. Gastroenterology 2011Tseng, Kao et al. Hepatology 2012Chen YC, et al. Clin Gastroenterol Hepatol 2011

qHBsAg & HCC risk

• HBsAg > 1000 IU/ml could predict HCC risk in HBeAg-negative patients, especially in those who have HBV DNA <2000 IU/ml

Tseng and Kao et al. Gastroenterology 2012Chen et al. AASLD 2011 Abstract 1095

Can we refine our risk stratification?REVEAL-HBV study: N=3653

14

10

6

4

2

00 1 2 3 4 5 6 7 8 9 10 11 12 13

Cum

ulat

ive

inci

denc

e of

HC

C (%

)

Years of follow-up

16

12

8

14.9%

12.2%

3.6%

1.4%1.3%

Baseline HBV-DNA (copies/mL)≥106

105–<106 >20,000 IU/ml104–<105 >2000 IU/ml300–<104

<300

Does HBV DNA provide the full picture?

Chen et al. JAMA 2006

HBsAg level is an important risk factor in patients with low HBV DNA level (<2000 IU/mL)

Tseng, Kao. Gastroenterology 2012; Chan HL. Gastroenterology 2012

ERADICATE-B (2688 HBV carriers)

5-fold risk increase by univariate analysis

HBsAg and LTx

qHBsAg & therapy

Treatment strategies of CHB

Sustained remission

=

Maintained remission

= Low viremia No viremia

ALT normalization ALT normalization

Immune control,no further need for

antiviral drugs

No immune control, continued need for

antiviral drugs

INTERFERON NAs

qHBsAg is the closest meaning we have to a ‘cure’ of Chronic Hepatitis B

qHBsAg appear to be correlated with intrahepatic cccDNA levels, that are a marker of HBV infected cells

Reduction of infected hepatocytes is the hallmark of stronger control of HBV infection, that is a pre-requisite to achieve a off therapy sustained response

qs HBsAg serum levels monitoring could become the best tool to tailor antiviral therapy

HBsAg kinetics during antiviralTreatment is a marker of:

1. Drug effectiveness

2. Viral suppression

3. Sustained control

HBsAg clearance

HBsAg & INF • IFN has limited direct antiviral efficacy but stimulates

the induction of a host immune response against HBV.

• A successful immune response causes the destruction of infected liver cells, resulting in a decline of intrahepatic HBV DNA.

• Studies have shown that the decline in qHBsAg during is associated with the induction of an effective anti-HBV immune response.

How can we improve PEG-IFN efficacy ?

• de-novo combination therapy • duration of therapy • pre-treatment predictors of response • on-treatment predictors of response

HBsAg & NAs

• NAs can induce and maintain undetectable levels of HBV DNA.

• NA act on HBV polymerase activity, which is separate from HBsAg production.

• Consequently, NA may induce pronounced DNA declines, their effect on serum HBsAg levels is very limited.

HBsAg loss with NAs

HBsAg loss following short-term NA therapy is rare Longer treatment– up to 5 years – may appear to improve S-Ag loss

However, there are recent reports of HBsAg loss with Tenofovir with add-on INF

(AASLD 2014 Liver Meeting HBV Coverage)

Future advances

Summary points & conclusions

• HBsAg levels probably provide a complementary information to HBV DNA .

• High levels of HBsAg and HBV DNA are indicative of a highly productive phase of HBV infection .

• On the other hand, very low levels of both markers are indicative of inactive HBV infection.

• During INF-based therapy, a decline in qHBsAg is used to predict response.

• In NA-based therapy, the current clinical applications for qHBsAg are limited and so, we need to study the qHBs-Ag kinetics during NA-based therapy.

• A great effort is needed to determine a tailored therapy by using these predictors of response

Mohamed Mekky

My best regardsDr. Mohamed A Mekky

doc_mekky0000@yahoo.com