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On-Treatment Decline in Serum HBsAg Levels Predicts Sustained Immune Control and HBsAg Clearance 6 Months Post-Treatment in HBeAg-Positive Hepatitis B Virus-Infected Patients Treated with Peginterferon Alfa-2a [40KD] (PEGASYS)
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Reported by Jules Levin
Presented at the 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), 25-28 March 2010, Beijing, China
Piratvisuth T,1 Lau GKK,2 Marcellin P,3 Brunetto MR,4 Kapprell H-P,5 Popescu M6
1NKC Institute of Gastroenterology and Hepatology, Department of Internal Medicine, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand;
2Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China; 3Service d'Hepatologie and Centre de Recherches Biologiques
Bichat Beaujon (Inserm CRB3), University of Paris, Clichy, France; 4UO Epatologia, Azienda Ospedaliero Universitaria Pisana, Pisa, Cisanello, Italy;
5Abbott GmbH & Co, Wiesbaden-Delkenheim, Germany; 6F. Hoffmann-La Roche Ltd, Basel, Switzerland
Summary
On-treatment HBsAg levels <1500 IU/mL were significantly associated with response; over half of all patients with HBsAg <1500 IU/mL at weeks 12 and 24 achieved sustained immune control 6 months post-treatment
Rates of HBsAg clearance were high in patients who had HBsAg <1500 IU/mL at weeks 12 or 24 and sustained immune control (18% and 20%, respectively)
Conclusion
Low levels of HBsAg during a finite course of peginterferon alfa-2a therapy in HBeAg-positive patients are associated with high rates of sustained immune control and HBsAg clearance - the closest outcome to clinical cure of CHB
On-treatment quantification of HBsAg levels during treatment with peginterferon alfa-2a can identify HBeAg-positive patients with a high chance of achieving sustained post-treatment response and HBsAg clearance. This may help guide patient management in the future, allowing physicians to better identify early during therapy the patients who are most likely to achieve long-term response
Background
In chronic hepatitis B (CHB), sustained immune control is associated with a range of beneficial effects and is a critical step towards hepatitis B surface antigen (HBsAg) clearance - the closest outcome to cure in CHB.1,2 In patients with hepatitis B e antigen (HBeAg)-positive CHB, HBeAg seroconversion represents the transition from the immune clearance phase to inactive CHB3 and, therefore, is a marker of sustained immune control
Follow-up data from patients included in a large phase 3 clinical trial showed that the rate of sustained immune control in patients treated with a finite course of peginterferon alfa-2a [40KD] (PEGASYS) increases over time post-treatment, rising from 27% at end of treatment to 32% 6 months post-treatment and 42% 1 year post-treatment4,5
Rates of HBsAg clearance were also seen to increase following a finite course of pegylated interferon therapy, reaching 11% at 3 years post-treatment6
The ability to identify, early during treatment, those patients who are likely to respond to treatment would be of considerable use to physicians. Results from recent pegylated interferon analyses suggest that on-therapy reduction in serum HBsAg levels may be a useful marker of response to therapy in patients with CHB7
Objective
To assess the association between on-treatment HBsAg levels and the likelihood of achieving sustained immune control (HBeAg seroconversion) and HBsAg clearance 6 months post-treatment with a 48-week course of peginterferon alfa-2a (PEGASYS)
Methods
HBeAg-positive patients (N=542) received peginterferon alfa-2a (180 µg/week) ± lamivudine (100 mg/day) or lamivudine alone (N=272) for 48 weeks as part of a large-scale phase 3 trial4
Quantitative HBsAg levels were analyzed retrospectively in stored sera from patients with available samples pre-treatment and at weeks 12, 24, 48 and 72 (N=399 for peginterferon alfa-2a ± lamivudine; N=149 for lamivudine) using the Abbott Architect HBsAg assay. Patients were categorized according to HBsAg levels at weeks 12 and 24 of treatment. Mean baseline HBsAg level was 4.13 ± 0.67 log10 IU/mL
The association between sustained immune control and/or HBsAg clearance 6 months post-treatment and HBsAg level during therapy (weeks 12 and week 24) was determined
Results
A finite course of peginterferon alfa-2a is associated with sustained immune control and HBsAg clearance
Of the 399 peginterferon alfa-2a ± lamivudine-treated patients included in the analysis, 31% (N=122) achieved sustained immune control (HBeAg seroconversion) 6 months post-treatment and 4% (N=17) achieved HBsAg clearance 6 months post-treatment
On-treatment HBsAg decline is greater with peginterferon alfa-2a than with lamivudine
The decline in HBsAg was more pronounced in patients receiving peginterferon alfa-2a either alone or in combination with lamivudine, than with lamivudine alone (Figure 1)
For subsequent analyses, data from the two peginterferon alfa-2a arms were pooled
Figure 1. On-treatment HBsAg decline is more pronounced in peginterferon alfa-2a ± lamivudine-treated patients than in patients treated with lamivudine alone
For peginterferon alfa-2a-treated patients, low on-treatment HBsAg levels are associated with high rates of sustained immune control and HBsAg clearance
Patients with low (<1500 IU/mL) HBsAg levels on-treatment at weeks 12 or 24 had significantly higher rates of sustained immune control than patients with higher HBsAg levels (P<0.0001 for <1500 IU/mL versus higher levels at both time points; Figure 2)
Sustained immune control was achieved by 57% of the patients with HBsAg <1500 IU/mL at week 12 and by 54% of those with HBsAg <1500 IU/mL at week 24 (Figure 2)
Figure 2. Peginterferon alfa-2a-treated patients with low on-treatment HBsAg levels achieve significantly higher rates of sustained immune control post-treatment
By week 12 of treatment, 23% (N=90) of peginterferon alfa ± lamivudine-treated patients had HBsAg levels <1500 IU/mL - this had increased to 34% (N=136) by week 24 of therapy (Figure 3)
Figure 3. The proportion of patients who achieve HBsAg levels <1500 IU/mL increases between weeks 12 and 24
High rates of HBsAg clearance 6 months post-treatment were seen in those patients who achieved HBsAg <1500 IU/mL at week 12 or 24 and sustained immune control (Figure 4)
- Of the 51 patients with HBsAg <1500 IU/mL at week 12 and sustained immune control, 18% (N=9) achieved HBsAg clearance 6 months post-treatment
- Of the 74 patients with HBsAg <1500 IU/mL at week 24 and sustained immune control, 20% (N=15) achieved HBsAg clearance 6 months post-treatment
Figure 4. Patients with low HBsAg levels on-treatment AND sustained immune control achieve a high rate of HBsAg clearance
References
1. EASL. EASL clinical practice guideline: management of chronic hepatitis B. J Hepatol 2009;50:227-242
2. van Zonneveld M et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 2004;39:804-810
3. Liaw YF. HBeAg seroconversion as an important endpoint in the treatment of chronic hepatitis B. Hepatol Int 2009;3 (epub ahead of publication; DOI:10.1007/s12072-009-9140-3)
4. Lau GKK et al. Peginterferon alfa-2a, lamivudine and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-2695
5. Lau GKK et al. Durability of response and occurrence of late response to peginterferon alfa-2a (40KD) (PEGASYS) one year post treatment in patients with HBeAg-positive chronic hepatitis B. Presented at:
41st Annual Meeting of the European Association for the Study of the Liver (EASL); April 26-30, 2006; Vienna, Austria
6. Buster EH et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alfa-2b. Gastroenterology 2008;135:459-467
7. Marcellin P et al. In patients with HBeAg-negative chronic hepatitis B, HBsAg serum levels early during treatment with peginterferon alfa-2a predict HBsAg clearance 4 years post-treatment. Hepatology 2008; 48(suppl 1):919A
Disclosure information: Editorial support for the development of this poster was funded by F. Hoffmann-La Roche, Basel, Switzerland
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