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HBsAg Seroconversion in Adefovir Treated Chronic Hepatitis B Patients
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Reported by Jules Levin
Mitch Shiffman (McGuire VAMC, Richmond VA, USA) reported these study results at the EASL Conference (April 14-18, 2004, Berlin, Germany). Here is his report.
This was one of a number of adefovir (ADV) studies presented at EASL, and you'll receive additional NATAP reports on these studies. Adefovir once daily dosing at 10 mg is FDA approved to treat HBV. In previous studies ADV has been shown to be active in patients with: HBeAg+, HBeAg-, and lamivudine resistant (YMDD) HBV. ADV has shown durable HBV DNA suppression with a high threshold for the development of resistance.
The clearance of circulating hepatitis B surface antigen (HBsAg) and appearance of antibody to HBsAg (anti-HBs) have been generally accepted as evidence of clinical and serologic recovery from chronic hepatitis B virus infection. HBsAg clearance in chronic Hepatitis B is delayed and infrequent: 1-2% per year in Western countries where HBV infection is usually acquired in adulthood; 0.05%-0.8% per year in endemic areas where HBV infection is mostly acquired vertically.
The aim of this study is to describe the frequency of HBsAg loss and seroconversion to anti-HBs in patients who were treated with ADV monotherapy in clinical trials, and factors that may influence HBsAg seroconversion.
Brief Summary: 9 patients achieved HBsAg seroconversion (1.9%) with ADV monotherapy after a median 0f 80 weeks. Seven patients were HBeAg+ and 2 patients were HBeAg- at baseline. Baseline median HBV DNA was 8.57 log10 copies/ml (range 4.27-9.78); median ALT was 112 IU/L (range 52-324). At the time of HBsAg seroconversion serum HBV DNA was undetectable by Roche Amplicor Monitor PCR (LLQ<1,000 copies/ml) and serum ALT was within normal limits in all patients. Of the 7 HBeAg+ patients, the median time from loss of HBeAg to HBsAg seroconversion was 32 weeks (range 16-88). Six of the 9 who seroconverted were Genotype A.
A retrospective analysis of all patients who received at least 4 weeks of ADV monotherapy in two clinical trials conducted between 1999-2001 was evaluated: study 437 was double-blinded, placebo controlled study in 344 HBeAG+ patients with compensated liver disease; study 438 was double-blinded, placebo controlled study in 125 HBeAg- patients with compensated liver disease. HBsAg seroconversion was defined as loss of HBsAg and appearance of anti-HBs at a single time point.
PARAMETERS ANALYZED
-Demographic characteristics
-Values at baseline:
--serology
--serum ALT
--serum HBV DNA
-Proportion with:
--undetectable serum HBV DNA (Roche Amplicor: LLQ=1,000 copies/ml)
--HBeAg loss
--normalization of ALT
-HBV Genotype
PATIENTS WITH HBsAg SEROCONVERSION
All patients had HBV DNA
TOTAL SEROCONVERTED: 1.9%
HBeAg- who seroconverted: 1.6%
HBeAg+ who seroconverted: 2.0%
HBeAg+
HBeAg loss and HBsAg Seroconversion
--27% (91/333) patients HBeAg+ achieved HBeAg loss*
--7% (6/91) of these 91 patients had HBsAg loss**
*HBeAg loss confirmed at two consecutive visits or at last visit prior to week 48
**all patients achieved HBeAg-lossprior to HBsAg seroconversion.
HBeAg-
Serum HBV DNA Reduction and HBsAg Seroconversion
--62% (77/125) of patients with serum HBV DNA <1000 copies/ml by week 48*
--3% experienced HBsAg seroconversion
*undetectable serum HBV DNA (<1000 copies/ml) confirmed at two consecutive visits or last visit.
MEDIAN TREATMENT DURATION
PRIOR TO HBsAg SEROCONVERSION
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HBeAg+
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HBeAg-
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n=7
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n=2
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Median weeks to
HBeAg loss (range)
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37
(32-55)
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NA
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Median weeks ADV
treatment Prior to HBsAg
seroconversion (range)
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48
(56-120)
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44
(16-73)
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Median weeks from HBeAg
Loss To HBsAg seroconversion
(range)
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45
(11-139)
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NA
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HBV GENOTYPE AT BASELINE in HBeAg+
and HBeAg LOSS in YEAR 1
and SEROCONVERSION
HBeAg+: n=344
HBeAg loss in year 1: n=101
HBsAg seroconversion: n=7
Genotype:
A: 28%; 31% with HBeAg loss were A; 86% of seroconversions were A
B; 22%; 17% with HBeAg loss were B; 0 seroconverted
C: 34%; 31% with HBeAg loss were C; 0 seroconverted
D: 13%; 13% with HBeAg loss were D; 0 seroconverted
3% of patients were Genotype E, F, and G
DURABILITY OF HBsAg SEROCONVERSION
HBsAg was durable off treatment:
--median followup was 80 weeks (range 27-121)
--one patient lost HBsAg+ but remained HBsAg-
All patients with HBsAg seroconversion maintained undetectable HBV DNA and normal ALT levels off treatment.
BASELINE CHARACTERISTICS for PATIENTS WITH HBsAg SEROCONVERSION vs OVERALL STUDY
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HBeAG+
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HBeAg-
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HBsAg-/HBsAb+
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HBsAg+
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HBsAg-/HBsAb+
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HBsAg+
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N
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7
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344
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2
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125
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Median age
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49
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32
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39
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47
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Male
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86%
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75%
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50%
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82%
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Caucasian
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86%
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36%
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100%
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70%
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Median HBV DNA(log copies/ml)
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8.98
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8.37
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6.51
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6.56
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Median ALT (IU/L)
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109
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95
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188
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99
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1 patient who seroconverted was Genotype G at baseline.
SUMMARY by authors:
HBsAg seroconversion with ADV therapy was
--durable off treatment
--associated with undetectable serum HBV DNA
(<1000 copies/ml) and ALT normalization
HBeAg seroconversion with ADV therapy is also durableOff treatment in >90% of patients (TT Chang et al, EASL 2004Poster #424)
Genotype A patients appear more likely to undergo HBsAg Seroconversion
Further surveillance in long-term studies out to 5 yrs is ongoing
CONCLUSIONS by authors:
HBsAg seroconversion observed in 1.9% of patients treated with ADV monotherapy; 6% of patients with Genotype A
HBsAg seroconversion was durable off treatment
All patients with HBsAg seroconversion maintained undetectable HBV DNA and normal ALT levels off treatment.
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