Results of 5-Year Post-Treatment Follow-up Treated With Peginterferon

HBsAg Decline Appears To Predict Clearance- 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

Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), 22-24 April 2009, Copenhagen, Denmark

Reported by Jules Levin

Marcellin P,1 Piratvisuth T,2 Brunetto M,3 Bonino F,4 Lau GKK,5 Farci P,6 Yurdaydin C,7 Gurel S,8 Wu J,9 Popescu M10 1Service d'Hepatologie, Hopital Beaujon APHP and Centre de Recherches Biologiques Bichat 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 90110, Thailand; 3UO Gastreonterologia ed Epatologia, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy; 4Scientific Direction, Foundation IRCCS Policlinico of Milan and University of Pisa, Italy; 5Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; 6Universita di Cagliari, Cagliari, Italy; 7University of Ankara, Faculty of Medicine, Ankara, Turkey; 8Department of Gastroenterology, Uludag University, Turkey; 9Roche, Dee Why, Australia; 10F Hoffman-La Roche, Basel, Switzerland

Author Summary
Treatment with peginterferon alfa-2a ± lamivudine can induce biochemical and virologic response in around 20% of patients 5 years post-treatment, with HBV DNA levels below a threshold considered to be associated with a reduced risk of progressive liver disease

Importantly, the rate of HBsAg clearance in peginterferon alfa-2a-treated patients continued to increase during long-term follow-up, reaching 12% 5 years post-treatment highlighting that peginterferon alfa-2a is associated with a long-term durable posttreatment response

The rate of HBsAg clearance at year 5 in patients with HBV DNA ≤400 copies/mL was 72%
HBsAg decline during treatment was significantly greater in patients with HBsAg clearance, than in those who did not clear HBsAg. These results suggest that quantification of HBsAg might be a useful on-treatment predictor of long-term HBsAg response

Analysis of HBsAg decline in patients with genotype D suggests that the rate of decline is slower in patients with genotype D. However, the rate of HBsAg clearance achieved in HBV genotype D patients 5 years post-treatment was similar to that observed in the overall study population.

Conclusions
A finite course of peginterferon alfa-2a induces sustained responses in patients with HBeAg-negative CHB and, importantly, the rate of HBsAg clearance - the closest outcome to clinical cure of CHB - increases post-treatment.

The current analysis has shown that HBsAg decline during treatment is associated with long-term response suggesting that quantification of HBsAg during treatment may be used to predict long-term response to peginterferon alfa-2a-based therapy. Patients infected with genotype D are considered to be harder to treat than others, however, this analysis clearly demonstrates that these patients achieve similar HBsAg clearance rates response rates to the overall study population

Background
HBsAg clearance or HBsAg seroconversion can be considered the closest we can achieve to clinical cure of chronic hepatitis B (CHB) infection

In a large phase 3 study in patients with HBeAg-negative CHB, HBsAg clearance was achieved 6 months post-treatment following 48 weeks of therapy with peginterferon alfa-2a ± lamivudine, but not with lamivudine alone1

Patients from this study were invited to take part in a long-term observational follow-up study; the 3-year post-treatment follow-up results were published recently2

Recent data have shown that patients treated with a 48-week course of peginterferon alfa-2a, with or without lamivudine, have a marked decline in HBsAg from baseline to end of treatment.3 That study demonstrated that HBsAg levels at the end of treatment are associated with HBsAg clearance 3 years post-treatment in patients treated with peginterferon alfa-2a ± lamivudine

Objective
In the current analysis we report the response to peginterferon alfa-2a ± lamivudine up to 5 years post-treatment and determine whether HBsAg levels during peginterferon alfa-2a therapy could be used to predict response 5 years post-treatment

Methods
HBeAg-negative patients received peginterferon alfa-2a (180 µg/week, N=177), peginterferon alfa-2a + lamivudine (100 mg/day, N=179), or lamivudine alone (N=181) for 48 weeks as part of a multicenter, international study (initial study). Patients were followed up for an additional 24 weeks and the endpoint of the initial study was 6 months post-treatment

All participating centers in the initial study were invited to participate in an observational followup study, in which patients were followed for up to 5 years after completion of treatment

The current analysis includes patients treated with peginterferon alfa-2a ± lamivudine who entered the follow-up study (N=230)

Parameters assessed over the 5-year follow-up period were:
· HBV DNA ≤10,000 copies/mL (~2000 IU/mL)*
· HBV DNA ≤400 copies/mL (~100 IU/mL)*
· HBsAg clearance
· HBsAg seroconversion
· ALT normalization

Quantitative HBsAg in serum was measured pre-treatment, on-treatment (weeks 12, 24 and 48) and 6 months post-treatment (week 72) using the Abbott Architect HBsAg assay in available stored sera

Additional analyses according to genotype were also conducted
* HBV DNA levels were measured using the COBAS AMPLICOR HBV MONITOR, which has a conversion factor of 1 IU/mL = 5.6 copies/mL

Results

Virologic and biochemical response at year 5

Of the 54 centers involved in the initial study, 42 participated in the long-term study - contributing 315 (59%) of the original 537 patients. Significantly more patients who received peginterferon alfa-2a ± lamivudine (66% and 64%, respectively) than lamivudine alone (47%; P <0.01 vs peginterferonalfa-2a ± lamivudine) in the initial study went on to participate in the long-term study

230 patients who had received peginterferon alfa-2a either alone or in combination with lamivudine and 85 patients who had received lamivudine alone participated

The long-term virologic and biochemical effects over time of a 48-week course of treatment with peginterferon alfa-2a ± lamivudine in patients participating in the long-term study are shown in Table 1

Normal ALT defined as 30 IU/L

Results from the 5-year analysis - HBsAg clearance and seroconversion

HBsAg clearance in patients treated with peginterferon alfa-2a ± lamivudine increased at each yearly assessment from 1-year post-treatment through to 5 years post-treatment (Figure 1)

A total of 14 patients treated with peginterferon alfa-2a alone and 14 patients treated with peginterferon alfa-2a + lamivudine cleared HBsAg (total of 28 patients, 12.2%). The numbers of lamivudine-treated patients in the follow-up study were small and, therefore, comparisons are problematic, but for reference the rate of HBsAg clearance in lamivudine-treated patients was 3.5% at year 5

HBsAg seroconversion was achieved by 16 (7.0%) peginterferon alfa-2a ± lamivudine-treated patients at year 5

All patients achieving HBsAg clearance at year 5 had HBV DNA ≤400 copies/mL, therefore, the rate of HBsAg clearance in patients with a sustained virologic response was 72%