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发表于 2004-9-8 01:50
A dose-finding study of once-daily oral telbivudine in HBeAg-positive
patients with chronic hepatitis B virus infection
Hepatology, Volume 40, Issue 3, September 2004
Ching-Lung Lai 1 *, Seng Gee Lim 2, Nathaniel A. Brown 3, Xiao-Jian
Zhou
3, Deborah M. Lloyd 3, Yin-Mei Lee 2, Man-Fung Yuen 1, George C.
Chao 3, Maureen W. Myers 3
1University of Hong Kong, Hong Kong, China
2Changi General Hospital, Singapore
3Idenix Pharmaceuticals, Cambridge, MA
Abstract
Current therapy for chronic hepatitis B is suboptimal as a result of
limited durable response rates, cumulative viral resistance, and/or
poor
tolerability. Telbivudine has potent antiviral activity against
hepatitis B virus (HBV) in vitro and in the woodchuck model and has a
promising
preclinical safety profile.
In this first clinical study of telbivudine, safety, antiviral
activity,
and pharmacokinetics were assessed in 43 adults with hepatitis B e
antigen-positive chronic hepatitis B. This placebo-controlled
dose-escalation trial investigated 6 telbivudine daily dosing levels
(25, 50, 100,
200, 400, and 800 mg/d); treatment was given for 4 weeks, with 12
weeks'
follow-up. Serum HBV DNA levels were monitored via quantitative
polymerase chain reaction.
The results indicate that telbivudine was well tolerated at all dosing
levels, with no dose-related or treatment-related clinical or
laboratory
adverse events. telbivudine plasma pharmacokinetics were
dose-proportional within the studied dose range.
Marked dose-related antiviral activity was evident, with a maximum at
telbivudine doses of 400 mg/d or more. In the 800mg/d cohort, the mean
HBV DNA reduction was 3.75 log10 copies/mL at week 4, comprising a
99.98% reduction in serum viral load.
A pronounced decline of serum HBV DNA occurred in all
telbivudine-treated patients over the 4-week treatment period (Fig. 1).
At 4 weeks,
treatment with 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, and 800 mg
telbivudine resulted in mean decreases from baseline of 2.5, 2.68,
3.19,
2.89,
3.63, and 3.75 log10 copies/mL, respectively, compared with a mean 0.13
log10 decrease in the placebo group. The lower-than-expected HBV
DNA reduction for the 200mg/d cohort, compared with the results for the
100mg/d cohort, may have been due to the lower baseline viremia
level in the 200mg/d group (i.e., 1.1 log10 lower than the 100mg/d
group).
Only one telbivudine-treated patient failed to achieve protocol-defined
virological response (i.e., a 2 log10 or greater reduction in serum HBV
DNA levels at week 4). This patient was in the lowest-dose group (25
mg/d) and exhibited a 1.2 log reduction in HBV DNA at week 4. No
placebo recipients achieved a 2 log10 reduction in HBV DNA levels;
therefore, virological response was significantly more common in
telbivudine recipients (97% vs. 0%, P < .0001). Posttreatment, serum
HBV
DNA levels returned toward baseline levels in an overall dose-related
manner, with the slowest return of viremia in the 400 and 800mg/d dose
groups.
Telbivudine was well tolerated at all doses. There were no serious
adverse events and no dose-limiting toxicities. All reported adverse
events
were mild or moderate in intensity, and most were not attributed to
study treatment. There was no appreciable pattern of dose-related or
treatment-related (telbivudine vs. placebo) clinical adverse events or
laboratory abnormalities.
Overall, the safety profile of telbivudine appeared comparable to
placebo. During treatment, increases in aminotransferases were the most
commonly observed grade 1 and 2 laboratory abnormalities. These were
observed at similar rates in the telbivudine and placebo patients. No
grade 4 abnormalities were seen during treatment, and the only grade 3
abnormalities observed were an episode of hyperglycemia in a placebo
patient and an elevated serum GGT level in a patient receiving 400 mg
telbivudine. During follow-up, one patient each in the 50-mg/d and
100-mg/d treatment groups experienced transient grade 3 elevation in
aminotransferases.
Correspondingly, posttreatment return of viral load was slowest in the
high-dose groups. Viral dynamic analyses suggested a high degree of
efficiency of inhibition of HBV replication by telbivudine and helped
refine selection of the optimal dose. In conclusion, these results
support
expanded clinical studies of this new agent for the treatment of
hepatitis B.
Article Text
Hepatitis B remains a significant global health problem. An estimated
350 million individuals with chronic hepatitis B virus (HBV) infection
are
at risk of progressive necroinflammatory liver disease. Natural history
studies indicate a link between level of persistent HBV replication and
disease progression to cirrhosis and/or hepatocellular carcinoma.
Correspondingly, numerous clinical studies of interferon and anti-HBV
nucleosides/nucleotides indicate that prolonged suppression of HBV
replication can reverse hepatic necroinflammation, and several studies
suggest that longer-term patient outcomes can improve with therapy.
Alpha-interferon, lamivudine, and adefovir dipivoxil have been
extensively studied for the treatment of patients with chronic
hepatitis
B. These
agents allow clinical management of many patients, but overall efficacy
and safety remain suboptimal. Interferon induces hepatitis B e antigen
(HBeAg) seroconversion in perhaps 20%-35% of patients with pretreatment
alanine aminotransferase (ALT) levels exceeding twice the upper
limit of normal. However, most patients fail to respond to interferon,
and some patients are not eligible for interferon treatment because of
advanced disease or concurrent medical conditions. Frequent side
effects
and a requirement for self-injection tend to limit enthusiasm for
interferon among patients and physicians.
Orally bioavailable agents that directly inhibit HBV replication have
improved treatment options for patients with hepatitis B. Treatment
with
lamivudine or adefovir suppresses viremia by 3-4 log10 after 1 year,
reduces hepatic necroinflammatory activity, and increases the
probability
of HBeAg seroconversion. Lamivudine is generally well tolerated except
for occasional ALT flares associated with discontinuation of treatment
or viral breakthrough. With adefovir, a 12% HBeAg seroconversion rate
was reported after 48 weeks of treatment in HBeAg-positive patients,
and while generally well tolerated at 10 mg/d, adefovir carries
warnings
for potentially severe posttreatment flares and potential
nephrotoxicity.
As expected for any antimicrobial agent, drug-resistant HBV variants
have been selected in patients receiving prolonged treatment with
lamivudine or adefovir. The cumulative risk for emergence of
lamivudine-resistant (YMDD-mutant) HBV strains increases to 50% or more
with 3
years of therapy in high-viremic HBeAg-positive patients. Drug
resistance occurs most often in patients with suboptimal initial viral
suppression. Although loss of therapeutic response is variable, liver
disease may resume after viral breakthrough with lamivudine,
occasionally
with severe ALT flares.
Adefovir resistance is associated with the emergence of N236T and
possibly A181V mutant HBV strains. The 2-year incidence of adefovir
resistance appears to be relatively infrequent in lower-viremic
HBeAg-negative patients. The development of resistance is also
associated with
increased ALT levels.
Further optimization of antiviral therapy for hepatitis B is needed to
improve rates of durable response with safe, orally bioavailable
agents.
More potent agents that offer more profound HBV suppression may improve
results for key efficacy end points such as HBeAg
seroconversion, ALT normalization, and liver histology while minimizing
drug resistance.
Telbivudine (-L-2-deoxythymidine, telbivudine) is an
orally-bioavailable
L-nucleoside with potent and specific antiviral activity against HBV in
vitro and in animal models. In woodchucks, telbivudine suppresses serum
HBV DNA by over 8 log10 copies/mL with 4 weeks of treatment.
telbivudine has no significant effect on human DNA polymerases 卤, ??
or ??or on mitochondrial function, and there have been no adverse
findings in preclinical animal toxicology studies at chronic dosing up
to 1,000 mg/kg/d.
This report describes a human phase I/II clinical trial of telbivudine.
The study was a double-blind, placebo-controlled dose-escalation study
of
the safety, antiviral efficacy, and pharmacokinetics over 4 weeks of 6
different daily doses of telbivudine in HBeAg-positive patients with
compensated chronic hepatitis B.
Study Design
The dose-escalation design involved sequential investigation of 6 daily
doses of telbivudine (25 mg, 50 mg, 100 mg, 200 mg, 400 mg, and 800
mg). At each dosing level, a cohort of 7 eligible patients with
HBeAg-positive chronic hepatitis B was randomized at a ratio of 6:1 to
receive
telbivudine or matching placebo once daily. Patients were treated for 4
weeks and followed for an additional 12 weeks after discontinuation of
treatment.
Pharmacokinetics of plasma telbivudine were evaluated over 8 hours
following the first dose and at steady state between weeks 2 and 4.
Plasma
levels of telbivudine were measured with a validated high performance
liquid chromatographic assay with mass spectrometric detection. The
assay lower limit of quantitation was 0.1 ug/mL, and intra- and
interday
precision and accuracy (percent deviation) were below 10%. Blood
samples for viral load measurement were obtained at baseline and weekly
through week 8, and thereafter every other week through week 16.
Serum HBV was quantified at the central study laboratory using the
COBAS
Amplicor polymerase chain reaction assay for HBV DNA (Roche
Diagnostics, Branchburg, NJ) (lower limit of detection: 300 genome
copies/mL).
The 6 different dosing levels were investigated sequentially. When at
least 6 patients from a dose cohort completed treatment through week 4,
escalation to the next higher dose was discussed and agreed upon by the
study investigators if one of the following criteria were met: (1) at
least 6 of 7 patients within the cohort had completed treatment through
week 4 without a protocol-defined dose-limiting toxicity or (2) 2
additional patients had completed treatment through week 4 if 2 of the
initial 7 patients had developed a dose-limiting toxicity.
Dose-limiting
toxicities were specified in the protocol as: a prothrombin time of
more
than 3 seconds above control; a serum albumin level less than 30 g/L;
grade 3 or greater elevation of total bilirubin, creatinine, or
amylase;
grade 4 ALT elevation (>10 ? baseline) with any evidence of hepatic
insufficiency; or any other grade 4 clinical or laboratory toxicity
considered by the investigator to be at least reasonably or possibly
related to
the study drug.
Patients
Eligible patients included adults 18 years of age or older, with
chronic
hepatitis B documented by the presence of hepatitis B surface antigen
in
the serum for at least 6 months prior to the start of the study. The
minimum serum HBV DNA level was 1 ? 107 copies/mL or more at
screening. Patients were documented to be HBeAg-positive for at least 1
month with serum ALT levels below 5 times the upper limit of normal.
Exclusion criteria included: history or evidence of decompensated liver
disease; pregnancy or breast-feeding; unwillingness to use a barrier
method of contraception; coinfection with hepatitis C or D virus or
human immunodeficiency virus; any prior nucleoside analogue treatment;
treatment with interferon or corticosteroids within 6 months of
baseline; a hemoglobin level of less than 6.2 mmol/L; an absolute
neutrophil
count of less than 1.5 ? 109/L; a platelet count of less than 100 ?
109/L; a creatinine level of more than 133 umol/L; serum amylase and
pancreatic amylase/lipase levels of more than 1.5 times the upper limit
of normal; an alpha-fetoprotein level of more than 20 ng/mL with
follow-up ultrasonographic features of hepatocellular carcinoma; other
clinically important diseases; or current abuse of alcohol or illicit
drugs.
Written informed consent was obtained from all patients. The trial was
approved by the Ethics Committees of the two trial centers and was
conducted under Good Clinical Practice standards, with local regulatory
authorization and Investigational New Drug authorization by the U.S.
Food and Drug Administration.
For efficacy analysis, the evaluable population was defined as all
patients who received the study drug for the entire 4-week treatment
period,
were at least 90% compliant with the study drug (determined by pill
count) and had no major protocol violations. The population for safety
assessments included all patients who received any amount of the study
drug.
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