Date post: | 20-Mar-2017 |
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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