1. clinicaloptions.com/hepatitis Serum HBsAg as a Predictor of Response to PegIFN in HBeAg-Positive Patients Slideset on: Chan HL, Wong VW, Chim AM, Chan HY, Wong GL, Sung JJ. Serum HBsAg quantification to predict response to peginterferon therapy of e antigen positive chronic hepatitis B. Aliment Pharmacol Ther. 2010;32:1323-1331. Quantitation of Serum HBsAg During Treatment Predicts Response to Peginterferon in HBeAg-Positive Hepatitis B This program is supported by educational grants from

2. clinicaloptions.com/hepatitis Serum HBsAg as a Predictor of Response to PegIFN in HBeAg-Positive Patients Background and Rationale  PegIFN confers limited therapeutic benefit in chronic hepatitis B– infected patients with genotype B or C –Many baseline factors associated with treatment response (eg, HBV DNA, ALT) have little predictive ability in genotypes B/C HBV –Better on-treatment predictors of response needed, especially for genotypes B/C HBV, to identify patients unlikely to respond to a full course of treatment  HBsAg quantitation correlates with hepatic concentration of covalently closed circular DNA, which is cleared via immune-mediated response [1,2] –Monitoring serum HBsAg may help predict response to HBV therapy  Current study assessed value of serum HBsAg titer as predictor of response to pegIFN therapy among HBeAg-positive patients chronically infected with genotypes B/C HBV [3] 1. Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758. 2. Chan HL, et al. Clin Gastroenterol Hepatol. 2007;5:1462-1468. 3. Chan HL, et al. Aliment Pharmacol Ther. 2010;32:1323-1331.

3. clinicaloptions.com/hepatitis Serum HBsAg as a Predictor of Response to PegIFN in HBeAg-Positive Patients Summary of Study Design [1]  HBeAg-positive patients who completed pegIFN therapy per protocol during previous clinical trials conducted at The Chinese University of Hong Kong [2-4] –32-48 wks of pegIFN with or without 1-2 yrs of lamivudine –Patients coinfected with HCV excluded  Analyses of stored serum samples –HBsAg quantitation performed at baseline, Month 3, Month 6, end of treatment, and 12 mos posttreatment (assay sensitivity: 0.05-250 IU/mL) –HBV DNA quantitation at baseline, Month 3, Month 6, end of treatment, and 12 mos posttreatment (range of detection: 10 2 -10 9 copies/mL) –HBV genotype  Sustained treatment response: HBeAg seroconversion and HBV DNA < 10,000 copies/mL through 12 mos posttreatment  ROC curves used to evaluate ability of HBsAg and HBV DNA at different time points during treatment to predict sustained response 1. Chan HL, et al. Aliment Pharmacol Ther. 2010;32:1323-1331. 2. Chan HL, et al. Ann Intern Med. 2005;142:240-250. 3. Chan HL, et al. Antiviral Ther. 2007;12:815-823. 4. Chan HL, et al. Antivir Ther. 2008;13:555-562.

4. clinicaloptions.com/hepatitis Serum HBsAg as a Predictor of Response to PegIFN in HBeAg-Positive Patients Main Findings  20 of 21 patients (95%) who achieved sustained response maintained HBeAg seroconversion through 5.2 yrs (± 1.8) posttreatment  2 patients (2%) achieved HBsAg clearance Chan HL, et al. Aliment Pharmacol Ther. 2010;32:1323-1331. Outcome Time BaselineMonth 3 Month 6 Month 8 Month 12 1 Yr Posttx Mean HBV DNA, log 10 copies/mL  Responders7.463.74 2.782.352.142.82  Nonresponders8.134.94 4.443.874.606.60 Median HBsAg, IU/mL  Responders32991096 202120615951  Nonresponders59225075 3497336014255015 Change in HBsAg, log 10 IU/mL  Responders---0.48-1.05 -0.73-0.95-0.72  Nonresponders---0.14-0.38 -0.57-0.48-0.19

5. clinicaloptions.com/hepatitis Serum HBsAg as a Predictor of Response to PegIFN in HBeAg-Positive Patients Main Findings  Both HBsAg and HBV DNA during treatment predicted for sustained response –Values at Month 6 more highly predictive than values at Month 3 based on areas under ROC curves FactorROC (95% CI)P Value HBV DNA, log 10 copies/mL  Month 00.67 (0.55-0.79).019  Month 30.69 (0.57-0.81).008  Month 60.78 (0.68-0.88)<.001 HBsAg, IU/mL  Month 00.64 (0.51-0.78).047  Month 30.73 (0.60-0.85).002  Month 60.77 (0.65-0.89)<.001 Reduction in HBsAg, log 10 IU/mL  Month 30.67 (0.55-0.79).017  Month 60.70 (0.58-0.83).005 Chan HL, et al. Aliment Pharmacol Ther. 2010;32:1323-1331.

6. clinicaloptions.com/hepatitis Serum HBsAg as a Predictor of Response to PegIFN in HBeAg-Positive Patients Main Findings  Serum HBsAg ≤ 300 IU/mL at Month 6 provided maximum sum of sensitivity (62%) and specificity (89%) for predicting sustained response among all HBsAg cutoffs assessed over time  HBsAg reduction > 1 log 10 IU/mL at Mo 6 provided good discrimination between responders and nonresponders  Combining serum HBsAg ≤ 300 IU/mL and HBsAg reduction > 1 log 10 IU/mL at Month 6 provided good predictive ability –Sensitivity: 43% – Specificity: 96% –PPV: 75%– NPV: 85%  Serum HBsAg ≤ 300 IU/mL and HBsAg reduction > 1 log 10 IU/mL at Month 6 combined into algorithm to guide treatment decisions Chan HL, et al. Aliment Pharmacol Ther. 2010;32:1323-1331.

7. clinicaloptions.com/hepatitis Serum HBsAg as a Predictor of Response to PegIFN in HBeAg-Positive Patients Summary of Key Conclusions  Combination of absolute HBsAg level ≤ 300 IU/mL and > 1 log 10 IU/mL decrease in HBsAg at Month 6 of therapy provided best prediction of sustained response to pegIFN-based treatment in HBeAg-positive patients with genotype B/C HBV –75% of patients who attain both HBsAg responses at Month 6 expected to attain sustained response to full course of pegIFN  Prospective studies warranted to evaluate prospective management strategies –Are patients who fail to attain either HBsAg response best managed by switching to or adding nucleos(t)ide analogues? –Do patients who attain only absolute HBsAg level ≤ 300 IU/mL benefit from extended pegIFN therapy? –Will adding on-treatment HBV DNA to algorithm further increase predictive ability of HBsAg quantitation? Chan HL, et al. Aliment Pharmacol Ther. 2010;32:1323-1331.