HIVandHepatitis.com Highlights from the
56th Annual AASLD Conference
 November 11 - 15, 2005 San Francisco, California

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Histologic Improvement in Patients with Chronic Hepatitis B after Treatment with Peginterferon alfa-2a (Pegasys) Monotherapy

The relationship between histologic improvement and sustained responses, as well as the baseline factors predictive of histologic improvement, were assessed in patients with chronic hepatitis B treated with peginterferon a-2a (pegIFN a-2a) [Pegasys] within two large randomized trials (one HBeAg-positive[1] and the other HBeAg-negative [2]) [3].

In both studies, patients were treated with 180 mcg once weekly plus oral placebo for 48 weeks. Histologic response was prospectively defined as a ³2 point reduction in the modified Histologic Activity Index (HAI) score 24 weeks post-treatment compared with the pre-treatment score (necroinflamation graded 0 to 18 and fibrosis 0 to 6).

Histologic response was achieved in 49% HBeAg-positive and 59% HBeAg-negative patients (plus 20% and 16% with no change or <2 point reduction, respectively). There was a significant association between sustained response and improvement in liver histology:

In the HBeAg-positive study (N=207), 73% patients experiencing HBe seroconversion (N=75) versus 36% patients without seroconversion (N=132=) achieved histologic response (p<0.001).  There was also association between histologic response and earlier HBe seroconversion.

In the HBeAg-negative study (N=143), 78% patients achieving a combined response (ALT normalization and HBV DNA suppression <20,000 cp/mL) versus 49% patients with no combined response attained histologic response (p=.002).

High baseline ALT levels (but no plasma HBV DNA) were associated with histologic response at 6 months off treatment with pegIFN a-2a in both studies.  Low HBeAg levels were also identified as predictive of histologic response among HBeAg-positive patients (table 1).

Table 1. Baseline factors predictive of histologic improvement: multivariate logistic regression analyses.

HBeAg-positive
N=207
OR (95% CI); p

HBeAg-negative
N=143
OR (95% CI); p

ALT levels, IU/L
(1 log increase)

 7.5 (2.7 – 21.1); <0.001 10.39 (2.06 – 52.5); 0.005

HBeAg levels, IU/mL 
(1 log decrease)

1.9 (1.3 – 2.8); 0.001

NA

In summary, histological improvement off therapy was associated with sustained serologic, virologic and biochemical responses among patients with chronic hepatitis B treated with pegIFN a-2a monotherapy (Pegasys), being elevation of ALT levels at baseline a factor predictive of histological benefit.

 

Durability of Response to PegIFN Monotherapy in Patients with HBeAg-negative Chronic Hepatitis B

Following the previous report on the treatment of HBeAg-negative chronic hepatitis B with peginterferon (pegIFN)-a-2a (Pegasys) [1], results of 12 month post-treatment follow-up were presented at the 56th AASLD meeting [2].

In the initial study, conducted in 13 countries, patients were randomized to receive for 48 weeks either pegIFN-a-2a 180 mcg once weekly plus oral placebo daily, pegIFN-a-2a 180 mcg once weekly plus lamivudine 100 mg daily, or lamivudine 100 mg daily.

HBV DNA suppression was assessed with two different cutoffs: 400 cp/mL and 20,000 cp/mL. Results at 6 months post-treatment showed superiority of the pegIFN-a-2a arms compared to the lamivudine arm, with no additional benefit conferred by lamivudine (Epivir-HBV).

In the present analysis, the durability of response to pegIFN-a-2a monotherapy in those patients who had achieved a sustained response 6 months post-treatment was evaluated. The 43% (76/177) of patients in the initial study achieved HBV DNA suppression < 20,000 cp/mL 6 months post-treatment. Of them, 56 participated in the long-term study.

There were missing data in 7 cases (13%). Eight out of the 56 (14%) subjects experienced a rebound of HBV DNA over 100,000 cp/mL, while 41 (73%) maintained levels below 100,000 cp/mL at 12 months after discontinuation of pegIFN-a-2a:

21% (12/56) had HBV DNA £400 cp/mL

36% (20/56) had HBV DNA £20,000 cp/mL

16% (9/56) had HBV DNA £100,000 cp/mL

Regarding HBsAg loss/seroconversion, 7 patients had achieved that goal by the end of the initial study (6 months post-treatment), and one additional patient did so between 6-12 months post-treatment. Therefore, 8 patients achieved HBsAg loss/seroconversion at 12 months of follow-up after treatment discontinuation (5% of the initial study population in an ITT analysis).

Among the factors evaluated, no clear predictors of sustained virologic response to pegIFN-a-2a were found, but there was a trend toward better response in patients with lower end-of-treatment HBV DNA levels, higher baseline ALT levels, and infection with HBV genotype C (vs. B and D).

In summary, 73% of patients with HBV DNA plasma levels < 20,000 cp/mL 6 months after discontinuing pegIFN-a-2 monotherapy treatment, maintained the virological response over the 6-12 month follow-up period, with no clear factors predicting sustained response identified. Only 21% had HBV DNA suppression below 400 cp/mL, and only a minority (5%) achieved complete response. Once again, it is evident how difficult-to-treat this infection is.

11/18/05

References

1. G K K Lau and others. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352:2682-95.

2. P Marcellin and others. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351:1206-17.

3. GKK Lau and others. Predictors of histologic improvement and relationship between sustained response and histology in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a (40KD) (PEGASYS®)q. 56th AASLD [Abstract 994].

4. P Marcellin and others. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351:1206-17.

5. P Marcellin and others. Factors associated with sustained virological response 1 year after treatment with peginterferon alfa-2a (40KD) (PEGASYS®) monotherapy for HBeAg-negative chronic hepatitis B. 56th AASLD [Abstract 976].