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DURABILITY OF HBeAg SEROCONVERSION AFTER ADEFOVIR DIPIVOXIL TREATMENT FOR CHRONIC HEPATITIS B
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T.T. Chang (National Cheng Kung University Hospital, Tainan, Taiwan) reported on this study at the EASL Conference (April 2004, Berlin, Germany) for the Intl Adefovir 481 Study Group (poster #424). Here is his report.
Adefovir (ADV) is dosed with one 10mg tablet taken once daily orally (dose is modified for creatinine clearance <50 mL/min). About 400 million people worldwide have chronic hepatitis B (CHB). Hepatitis B "e" antigen (HBeAg) seroconversion in HBeAg+ patients is associated with prolonged suppression of viral replication and normalization of ALT. HBeAg seroconversion was durable off-treatment in 60-80% of lamivudine-treated chronic hepatitis B patients (Dienstag et al, Hepatology 2003 Apr;37(4):748-55). Interferon-induced HbeAg seroconversion has also been shown to be durable in 80-90% of chronic hepatitis B (Van Nunen et al, Gut 2003 Mar;52(3).420-4).
The objectives of this study are to evaluate the durability of HBeAg seroconversion (lossof HBeAg and gain of HBeAb) in patients with CHB after discontinuation of ADV treatment. To evaluate the effect of time on ADV treatment pre- and post- HBeAg seroconversion on durability in patients with CHB. To evaluate the effect of HBV genotype on the maintenance of HBeAg seroconversion in patients with CHB.
BRIEF SUMMARY. The authors concluded: HBeAg seroconversion achieved with ADV therapy was durable off-treatment for 91% of patients. Durable HBeAg seroconversion is associated with HBV DNA levels <1,000 copies/ml and normal ALT. Seroreversion is associated with increases in both serum HBV DNA and ALT. Preliminary results suggest duration of ADV treatment beyond seroconversion influences durability. All patients who underwent full seroconversion were genotype C. Further analysis is ongoing to evaluate other factors that may influence HBeAg seroconversion durability.
KEY INCLUSION CRITERIA
Compensated liver function.
HIV, HCV, and HDV seronegative.
HBeAg positive prior to start of ADV treatment in previous ADV studies.
HBeAg seroconversion in previous ADV study (defined as loss of HBeAg and appearance of HBeAb (confirmed on two consecutive visits at least 4 weeks apart).
STUDY DESIGN
This is a multi-center, multi-national, long-term, off-treatment observational study. Patients originated from 2 prior ADV studies (n=66):
--GS-98-437: phase 3, double-blind, randomized, placebo-controlled study in HBeAg positive patients (n=65)
--GS-96-412: phase 2 study (n=1)
Patients visits were every 4 weeks for the first 16 weeks, then every 24 weeks.
LAB ASSESSMENTS
Clinical assessments
--safety
--serum HBV DNA: Roche Amplicor PCR (LLQ <1,000 copies/ml)
--ALT and AST
--HBV serology: HBeAg (Diasorin ETI-EBK Plus); HBeAb Diasorin ETI-AB-EBK Plus) Virology analysis
--HBV genotype at baseline
--INNO-LIPA HBV pre-core assay used for detection of pre-core and core promoter mutations at baseline and upon loss of HBeAb.
RESULTS
DEMOGRAPHICS and DISEASE CHARACTERISTICS at ADV DISCONTINUATION
| N=66 | | Race | | | --Asian | 77% | | --Caucasian | 21% | | --Black | 2% | | Male | 65% | | Median age (range) | 34 (22-63) | | Median Duration of ADV | 53 weeks | | HBV DNA <1000 c/ml | 86% | | ALT <=ULN* | 89% |
*ULN=43 IU/L (males)/
34 IU/L (females)
HBV GENOTYPE at ADV INITIATION
Genotype A: 12 patients, 18%
B: 12 pts; 18%
C: 34 pts; 52%
D: 5 pts; 7%
G: 2 pts; 3%
Missing: 1 pt; 2%
DURABILITY of HBeAg SEROCONVERSION (HBeAg-/HBeAb+) FOLLOWING ADV DISCONTINUATION
Median duration off ADV therapy: 55 weeks (range 5-114).
All patients who did not maintain seroconversion were genotype C.
91% (n=60) maintained seroconversion (HBeAG-/HBeAb+)
3% (n=2) were HBeAg-/HBeAb-)
6% (n=4) were HBeAg+/HBeAb-
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DURATION of ADV THERAPY and SEROCONVERSION
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Maintained Seronconversion N=60
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HBeAb loss* n=6
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p-value
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Median Weeks on ADV pre-seroconversion (range)
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53 (4-192)
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108 (64-130)
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0.0113
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Median weeks on ADV post-seroconversion (range)
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48 (5-136)
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23 (20-61)
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0.0216
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SERUM HBV DNA and ALT LEVELS off ADV
| At entry into off-treatmrent follow-up | At last observation | | Median HBV DNA* Log10 copies/ml | 3.00 | 3.35 | | Median ALT (IU/L)** | 24 | 26 |
*LLQ<1,000 copies/ml
**ULN=43 IU/L (males; 34 IU/L (females)
HBV and ALT PROFILES for 4 PATIENTS WHO REVERTED to HBeAg+/HBeAB-
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HBV and ALT PROFILES for 2 PATIENTS WHO REVERTED to HBeAg-/HBeAb-
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Core Promotor and Pre-Core Mutations in the Four Patients Who Seroreverted
| Baseline | At loss of HBeAb | | Core promoter mutation | 3 (50%) | 4 (66%) | | Pre-core mutation | 1 (17%) | 1 (17%) | | Both promotor & Pre-core mutation | 2 (33%) | 1 (17%) |
The pattern of pre-core or core promotor mutations in patients who seroreverted remained similar over the course of follow-up.
SAFETY
No serious adverse events off therapy, with a median of 55 weeks off therapy follow-up (5-114 weeks).
ALT flares (>=10 x ULN) were seen in 3 patients (4%) following ADV discontinuation:
--all 3 patients maintained seroconversion
--ALT elevations were not associated with other signs of worsening liver function
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