clinicaloptions.com/hepatitisSerum 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

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clinicaloptions.com/hepatitisSerum 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.

clinicaloptions.com/hepatitisSerum 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: 102-109 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.

clinicaloptions.com/hepatitisSerum 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

Baseline Month 3

Month 6

Month 8

Month 12

1 Yr Posttx

Mean HBV DNA, log10 copies/mL

Responders 7.46 3.74 2.78 2.35 2.14 2.82

Nonresponders 8.13 4.94 4.44 3.87 4.60 6.60

Median HBsAg, IU/mL

Responders 3299 1096 202 1206 15 951

Nonresponders 5922 5075 3497 3360 1425 5015

Change in HBsAg, log10 IU/mL

Responders -- -0.48 -1.05 -0.73 -0.95 -0.72

Nonresponders -- -0.14 -0.38 -0.57 -0.48 -0.19

clinicaloptions.com/hepatitisSerum 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

Factor ROC (95% CI) P Value

HBV DNA, log10 copies/mL

Month 0 0.67 (0.55-0.79) .019

Month 3 0.69 (0.57-0.81) .008

Month 6 0.78 (0.68-0.88) < .001

HBsAg, IU/mL

Month 0 0.64 (0.51-0.78) .047

Month 3 0.73 (0.60-0.85) .002

Month 6 0.77 (0.65-0.89) < .001

Reduction in HBsAg, log10 IU/mL

Month 3 0.67 (0.55-0.79) .017

Month 6 0.70 (0.58-0.83) .005Chan HL, et al. Aliment Pharmacol Ther. 2010;32:1323-1331.

clinicaloptions.com/hepatitisSerum 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 log10 IU/mL at Mo 6 provided good discrimination between responders and nonresponders

Combining serum HBsAg ≤ 300 IU/mL and HBsAg reduction > 1 log10 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 log10 IU/mL at Month 6 combined into algorithm to guide treatment decisions

Chan HL, et al. Aliment Pharmacol Ther. 2010;32:1323-1331.

clinicaloptions.com/hepatitisSerum 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 log10 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.