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39th Annual European Association for the Study of the Liver Conference
Berlin, Germany
April 14-18, 2004
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Results of a 1-Year International Phase IIB Trial of LdT, and LdT plus Lamivudine, in Patients with Chronic Hepatitis B
  Results of a 1-Year International Phase IIB Trial of LdT, and LdT plus Lamivudine, in Patients with Chronic Hepatitis B
Reported by Jules Levin
Brief summary. LDT reduced HBV DNA (viral load) by 6 log by week 24 and maintained suppression at week 52 compared to 4.50 log for Lamivudine. 61% of patients receiving LDT monotherapy were PCR negative at week 52 compared to 32% for Lamivudine. ALT normalization was significantly better than for Lamivudine.. No identified safety issues (all treatments well tolerated). Exploratory analysis suggests that maximal early antiviral effect appears predictive of best outcome (maximal efficacy): HBeAg response; ALT normalization; viral clearance; minimizing viral breakthrough. Phase III study of LDT underway. DRUG RESISTSNCE: 4.6% of patients receiving LDT and 12.2% receiving LDT+LAM had resistance after one year therapy. See detailed report below. There was no evidence in this study for added benefit of combining LDT and Lamivudine. This does not necessarily mean that combining other HBV therapies will not produce added benefit, as combination studies are expected to be conducted.
Note from Jules Levin: It appears the different HBV studies for various HBV drugs have used different HBV DNA assays with varying lower limits & upper limits of quantification. This makes it difficult to compare across studies the absolute reductions in HBV DNA and the proportions below detection.
Authors: S.H. Han (UCLA School of Medicine, Los Angeles CA, USA) and colleagues reported results from this study at EASL (April 14-18, 2004, Berlin, Germany). Here is his report.
350-400 million people worldwide are chronic HBV carriers. It's endemic in Asia, equatorial Africa, and other regions. About 25-50% have active liver disease. Spontaneous remission occurs in 2-15% annually. HBV replication and liver disease can reactivate. 15-40% of carriers die of endstage liver disease (>1 million deaths/year). Persistent HBV replication is associated with liver disease. Han said that potent, sustained suppression of HBV replication is likely to be key to optimal treatment efficacy, but when to begin therapy and with what are important questions?
LdT (Telbivudine) is a specific inhibitor of HBV polymerase (not active against HIV or other viruses). It has favorable preclinical toxiciloy. Once daily oral dosing is indicated by PK. Phase I/II dose escalation results show:
--marked HBV suppression after 4 weeks: 3.4-3.8 log reduction with 400-800 mg/day
--excellent safety: no dose related or dose limiting toxicities
This randomized multicenter 52-week study compared the 1-year efficacy and safety of LdT 400 or 600 mg/day, and LdT 400 or 600 mg/day combined with lamivudine 100 mg/day, to lamivudine 100 mg/day in adults with HBeAg-positive CHB and baseline ALT >1.3 xULN. The primary endpoint was serum HBV DNA reduction, assayed by PCR. Key secondary endpoints included serum ALT normalization, HBeAg response, and safety.104 patients were enrolled at 16 sites in Honk Kong, Singapore, US, Canada, France. Interim analysis of data at week 12 and 24.
Male: 91%; Ethnicity: 85% Asian; 9% Caucasian; 3% Black; 3% other. Route of transmission: 64% maternal; 10% horizontal; 25% unknown. Mean age: 37 yrs. Overall mean weight: 70 kg.
--19-21 patients randomized to each treatment group, (small study).
--100% HBsAg+ at screening.
--100% HBeAg+ at screening
--Serum HBV DNA (median log copies/ml): 8.96 to 9.28
--Serum ALT (IU/L): 122-152
(different doses combined)
N=19 n=44 n=41
-Mean change (log copies/ml) -4.57 -6.01 -5.98
-Median Change -4.98 -6.34 -6.06
-Mean AUC Week 0-52 -4.42 -5.55 -5.80
-% patients HBV DNA negative\by PCR 32% 61% 49%

88% LDT
63% LAM
HBeAg Response at Week 52
N=44 n=22 n=41
HBeAg Loss 33% 28% 17%
HBeAg Seroconversion 31% 4% 15%


At least one AE was experienced equally across all LAM (n=13), LDT (400 & 600mg), n=15, and LDT 400/600 + LAM treatment groups n=20.
GRADE 3 & 4 Lab Toxicity(number of patients with event by week 52)
ALT flare 0 0 1 0 0
Lipase elevation 0 0 0 0 0
Absolute neutrophil 0 0 0 0 0
CPK elevation* 0 1 3 0 1

*patients continued treatment uninterrupted (except for 1 patient); most events resolved spontaneously by last followup--One patient with grade 3 neutropenia was low at screen
HBV DNA from patients with confirmed (2-point) virologic breakthrough was amplified by PCR and analyzed by DNA sequencing:
Total W52 Breakthru Genotypes
n M204I L180M+ M204V WT
LAM 19 4 (21.1%) 2 1 1*
LDT 44 2 (4.6%) 2
LDT+LAM 41 5 (12.2%) 3 1 1*

*may indicate noncompliance
EXPLORATORY ANALYSIS of Combined Patient Data
All patients grouped according to serum HBV DNA level at week 24 (Cobas Amplicor PCR). To investigate relationship of early viral suppression to efficacy outcomes at week 52.
HBeAg response at week 52: relationship to serum HBV DNA at week 24
This study found that efficacy response rates at week 52 were highest in patients with the most profound viral suppression at week 24. The study found that patients with better viral response at week 24 had better rates of HBeAg loss at week 52. The study authors reported that their analysis suggests that maximizing early suppression of HBV replication in patients with chronicHBV may enhance viral clearance, ALT normalization, and HBeAg response, and minimize resistance. HBeAg response was particularly sensitive to early viral suppressionin this analysis. HBeAg response rates at 1 year were the highest in patients who were PCR-negative at 24 weeks (<200 copies/ml), and were proportionately lower in other residual viremia categories. This observation is consistent with the emerging perception that a primary goal of therapy should be to reduce viral load ti the lowest possible level.
47% of of patients below QL (below quantification limit (<200 copies/ml) at week 24 had HBeAg response at week 52; they did not say if this was e loss or e loss plus seroconversion.
39% of patients with 3 log serum HBV DNA at week 24 had HBeAg response at week 52.
10% of patients with 3-4 log serum HBV DNA at week 24 had HBeAg response at week 52.
7% of patients with >4 log serum HBV DNA at week 24 had HBeAg response at week 52.
Exploratory Analysis of Combined Patient data
HBV DNA @wk24 BQL QL-103 103-104 >104
HBeAg Response 47% 38% 10% 7%
PCR Non-Detect 100% 62% 23% 7%
ALT normal 90% 88% 71% 56%
Viral breakthrough 0 0 19% 26%