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On-Treatment Decline in Serum HBsAg Levels Predicts Sustained Immune Control 1 Year Post-Treatment and Subsequent HBsAg Clearance in HBeAg-Negative 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
Marcellin P,1 Piratvisuth T,2 Brunetto M,3 Bonino F,4 Farci P,5 Yurdaydin C,6 Gurel S,7 Kapprell H-P,8 Messinger D,9 Popescu M10
1Service d'Hepatologie and Centre de Recherches Biologiques Beaujon (Inserm CRB3), University of Paris, Clichy, France; 2NKC Institute of Gastroenterology and Hepatology, Department of Internal Medicine, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand; 3UO Gastroenterologia ed Epatologia, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy; 4Scientific Direction, Foundation IRCCS Policlinico of Milan and University of Pisa, Italy; 5Universita di Cagliari, Cagliari, Italy; 6University of Ankara, Faculty of Medicine, Ankara, Turkey; 7Department of Gastroenterology, Uludag University, Turkey; 8Abbott GmbH & Co, Wiesbaden, Germany; 9IST GmbH, Mannheim, Germany; 10F. Hoffmann-La Roche Ltd, Basel, Switzerland
Summary
Sustained immune control 1 year post-treatment was achieved by 31% of HBeAg-negative patients treated with peginterferon alfa-2a. These patients achieved high rates of HBsAg clearance 5 years post-treatment (28% versus 12% of the overall study population)
An on-treatment decline in HBsAg ≥10% from baseline was significantly associated with sustained immune control at 1 year post-treatment and HBsAg clearance 5 years post-treatment
Highest rates of HBsAg clearance (40-45%) were achieved by patients with an HBsAg decline ≥10% during treatment and sustained immune control 1 year post-treatment
Conclusion
Decline in HBsAg during a finite course of peginterferon alfa-2a therapy in patients with HBeAg-negative CHB was associated with high rates of sustained immune control and HBsAg clearance up to 5 years post-treatment. Rates of HBsAg clearance 5 years post-treatment were highest in patients with at least a 10% decline in HBsAg during treatment and sustained immune control post-treatment. HBsAg quantification can be used to better identify early during therapy the patients who are most likely to achieve long-term sustained immune control and clearance of HBsAg - the closest outcome to clinical cure of CHB - thereby avoiding potentially life-long therapy and long-term costs
Background
Sustained suppression of HBV DNA to below 10,000 copies/mL (=2000 IU/mL) in hepatitis B e antigen (HBeAg)-negative patients treated with interferon-based therapy can be considered to represent sustained immune control of the virus as levels below this are found during the inactive phase of the disease. Achievement of sustained immune control is important as it is associated with a range of long-term benefits including a decreased risk of cirrhosis and hepatocellular carcinoma1,2
Patients who have a sustained response to interferon-based therapy have an increasing chance of achieving hepatitis B surface antigen (HBsAg) clearance - the ultimate goal of therapy in chronic hepatitis B (CHB) - during long-term follow-up3
Long-term follow-up of patients with HBeAg-negative CHB enrolled in the large phase 3 clinical trial of peginterferon alfa-2a [40KD] (PEGASYS) ± lamivudine has shown that a finite course of treatment with peginterferon alfa-2a can result in sustained immune control up to 5 years post-treatment4, 5
In addition, a high proportion of patients who achieve sustained immune control at
1 year post-treatment with peginterferon alfa-2a go on to achieve HBsAg clearance 5 years post-treatment4
Recent analyses have shown that patients who respond to peginterferon alfa-2a have greater decreases in HBsAg during treatment than non responders, suggesting that on-therapy reduction in serum HBsAg level may be a useful marker of response to therapy6
Objective
To assess the association between on-treatment HBsAg decline and the likelihood of achieving sustained immune control 1 year post-treatment and eventual HBsAg clearance following treatment with peginterferon alfa-2a (PEGASYS)
Methods
Patients with HBeAg-negative CHB received peginterferon alfa-2a (180 µg/week) ± lamivudine (100 mg/day) for 48 weeks and were followed up for 6 months post-treatment as part of a large-scale phase 3 study7
A total of 230 patients entered a long-term observational follow-up study and were followed for up to 5 years post-treatment; available data from these patients were included in this analysis
Quantitative HBsAg levels in serum were measured pre-treatment, on-treatment (weeks 12, 24, 48) and post-treatment (week 72) in available stored sera using the Abbott Architect HBsAg assay
The association between on-treatment HBsAg decline and rates of sustained immune control (HBV DNA ≤10,000 copies/mL) at 1 year post-treatment and HBsAg clearance at 5 years post-treatment were determined
Results
Peginterferon alfa-2a therapy is associated with sustained immune control and HBsAg clearance
- Of the 230 patients included in the long-term follow-up study, 72 (31%) achieved sustained immune control 1 year post-treatment and 28 (12%) had cleared HBsAg 5 years post-treatment
- Of the 72 patients achieving sustained immune control at 1 year post-treatment, 20 (28%) went on to achieve HBsAg clearance 5 years 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 all 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
On-treatment HBsAg decline during peginterferon alfa-2a therapy is significantly associated with sustained immune control and HBsAg clearance
- Sustained immune control 1 year post-treatment was significantly associated with HBsAg decline ≥10% from baseline at weeks 12 and 24 (P=0.0005 and P=0.0078 for weeks 12 and 24, respectively; Figure 2)
- Sustained immune control was achieved by 47% of the patients with an HBsAg decline from baseline ≥10% at week 12 and by 43% of those with an HBsAg decline from baseline ≥10% at week 24 (Figure 2)
Figure 2. HBsAg decline from baseline is significantly associated with sustained immune control at 1 year post-treatment*
*In patients with available sera for retrospective HBsAg testing at all time points (N=120). Baseline HBsAg = 3.40 ± 0.61 IU/mL
At week 12, 44% (53/120) of patients* had a ≥10% decline in HBsAg level from baseline. By week 24, 56% (67/120)* had achieved this level of decline (Figure 3)
Figure 3. The proportion of patients who achieve an HBsAg decline from baseline ≥10% increases between weeks 12 and 24*
Rates of HBsAg clearance 5 years post-treatment were significantly associated with HBsAg decline ≥10% from baseline at weeks 12 and 24
- Of the patients with a ≥10% HBsAg decline from baseline at week 12, 23% (12/53) cleared HBsAg 5 years post-treatment compared with 7% (5/67) with <10% decline (P=0.0161)
- Of the patients with a ≥10% HBsAg decline from baseline at week 24, 22% (15/67) cleared HBsAg 5 years post-treatment compared with 4% (2/53) with <10% decline (P=0.048)
Highest rates of HBsAg clearance 5 years post-treatment were seen in those patients who achieved a ≥10% decline from baseline in HBsAg at week 12 or 24 and sustained immune control at 1 year post-treatment (Figure 4)
- 40% (10/25) of patients with a ≥10% decline in HBsAg from baseline at week 12 and sustained immune control 1 year post-treatment achieved HBsAg clearance at year 5 post-treatment (Figure 4A)
- 45% (13/29) of patients with a ≥10% decline in HBsAg from baseline at week 24 and sustained immune control 1 year post-treatment achieved HBsAg clearance at year 5 post-treatment (Figure 4B)
Figure 4. Patients with low HBsAg levels on-treatment AND sustained immune control achieve a high rate of HBsAg clearance: A) week 12; B) week 24
References
1. EASL. EASL clinical practice guideline: management of chronic hepatitis B. J Hepatol 2009;50:227-242
2. Chen C-J et al. Long-term outcomes in hepatitis B: the REVEAL-HBV study. Clin Liver Dis 2007;11:797-816
3. Marcellin P et al. Increasing rates of HBsAg clearance and seroconversion in patients with HBeAg-negative disease treated with peginterferon alfa-2a ± lamivudine: results of 5-year post-treatment follow-up. J Hepatol 2009;50(suppl 1):S336
4. Marcellin P et al. A finite course of peginterferon alfa-2a results in inactive chronic hepatitis B and HBsAg clearance 5 years post-treatment in patients with HBeAg-negative disease: baseline characteristics and predictive factors of long-term response. Hepatology 2009;50(suppl 4):129A
5. Marcellin P et al. Sustained responses in patients with HBeAg-negative chronic hepatitis B 3 years after treatment with peginterferon alfa-2a. Gastroenterology 2009;136:2169-2179
6. Marcellin P et al. Quantitative HBsAg for early prediction of response to PEGASYS therapy in patients with early HBeAg-negative disease. Hepatol Int 2009;3(1):27
7. Marcellin P et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. New Engl J Med 2004;351:1206-1217
Disclosure information: Editorial support for the development of this poster was funded by F. Hoffmann-La Roche, Basel, Switzerland
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