Long-term
Data Show Telbivudine (Tyzeka) Suppresses HBV Viral Load
and Leads to HBeAg Clearance in Chronic Hepatitis B Patients
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| SUMMARY:
At the 60th Annual Meeting of the American Association
for the Study of Liver Diseases (AASLD
2009) this month in Boston, researchers reported
4-year data from the GLOBE study, indicating that
the nucleoside analog telbivudine
(Tyzeka) continues to provide long-term viral
load suppression, ALT normalization, and hepatitis
B "e" antigen (HBeAg) seroconversion
in chronic hepatitis
B patients. Another study showed sustained
response up to 2 years after completing telbivudine
treatment. |
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By
Liz Highleyman
GLOBE
was an international Phase 3 trial comparing 600 mg/day
telbivudine
versus 100 mg/day lamivudine
(Epivir-HBV) for 2 years in 1367 chronic hepatitis B
patients with compensated liver disease.
As
previously reported, at the end of the randomized part
of the study, participants taking telbivudine were significantly
more likely to experience treatment response than those
taking lamivudine, with 63% of HBeAg positive patients and
78% of HBeAg negative patients achieving undetectable HBV
DNA.
After
completion of the randomized part of the trial, participants
were given the option to continue telbivudine treatment
for a further 2 years in an open-label extension study to
evaluate the drug's long-term safety and efficacy. Y. Wang
and colleagues presented 4-year results at the AASLD meeting
(abstract 482).
A
total of 426 telbivudine recipients (236 HBeAg positive
and 190 HBeAg negative) elected to continue in the extension
study. None had genotypic resistance to telbivudine at the
end of the initial trial. Of these patients, 355 (83%) completed
4 years of therapy. The per-protocol population consisted
of 398 patients (213 HBeAg positive and 185 HBeAg-negative).
Results
 |
Among
the 213 HBeAg positive patients who completed 4 years
of continuous telbivudine treatment, 79% had undetectable
HBV DNA (< 300 copies/mL). |
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86%
achieved normal serum ALT levels. |
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55%
experienced HBeAg loss and 42% achieved HBeAg seroconversion.
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Patients
with undetectable HBV DNA at treatment week 24 in the
initial trial were more likely to achieve undetectable
viral load (92%) and HBeAg seroconversion (51%) at 4
years. |
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Among
185 HBeAg negative patients who received continuous
telbivudine, 84% had undetectable HBV DNA at 4 years.
" 91% had normal serum ALT. |
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The
telbivudine safety profile during the extension study
was similar to the 2-year findings, and no new safety
signals were observed with continued treatment. |
|
16%
of patients reported grade 3-4 creatine kinase elevation
(a marker of possible muscle damage), 6% experienced
grade 3-4 myalgia (muscle pain), and 0.5% each developed
serious myopathy (muscle disease) and myositis (muscle
inflammation). |
|
3%
of patients experienced ALT flares (sudden worsening
of liver inflammation). |
These findings led the investigators to conclude, "In
HBeAg positive and HBeAg negative chronic hepatitis B patients,
4 years of telbivudine treatment provides effective viral
suppression and ALT normalization with a favorable safety
profile."
Moreover,
they added, "telbivudine achieves a high seroconversion
rate in HBeAg positive patients."
HBsAg
as a Predictive Factor
In
a related study (abstract 487), German researchers
investigated serum hepatitis B surface antigen (HBsAg) levels
over 3 years of telbivudine treatment in 162 HBeAg positive
and 143 HBeAg negative patients who completed the telbivudine
arm of the GLOBE trial, achieved undetectable HBV DNA, and
were enrolled in the extension study for at least 52 weeks.
Results
|
The
researchers observed a significant correlation between
baseline serum HBsAg and HBV DNA levels among both HBeAg
positive and HBeAg negative patients. |
|
Telbivudine
treatment reduced HBsAg levels from baseline to year
3 in both groups. |
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Among
HBeAg positive patients, the main HBsAg decline occurred
during the first year of treatment. |
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In
HBeAg negative participants, in contrast, the main HBsAg
decline was observed at later time points, between years
2 and 3 of treatment. |
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At
24 weeks, 3 patterns of HBsAg kinetics were observed: |
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Rapid
decline > 0.5 log10 IU/mL in 53 HBeAg positive
and 11 HBeAg negative patients; consecutive HBsAg
loss at year 3 was observed in 7 HBeAg positive
patients and 1 HBeAg negative participant. |
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Slow
decline in 48 HBeAg positive and 59 HBeAg negative
patients; consecutive HBsAg loss at year 3 was
observed in 2 HBeAg positive patients and 1 HBeAg
negative patient; |
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Static
HBsAg levels in 61 HBeAg positive and 73 HBeAg
negative patients. |
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A
majority of patients with HBsAg loss at year 3 showed
rapid decline through week 24. |
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Strong
HBsAg decline up to week 24 was associated with a significantly
higher probability of subsequent HBsAg loss in both
HBeAg positive and HBeAg negative participants. |
Based
on these findings, the investigators concluded, "Baseline
serum HBsAg correlates with HBV DNA levels in HBeAg positive
and HBeAg negative patients."
"Telbivudine
treatment reduces serum HBsAg levels in HBeAg positive and
HBeAg negative chronic hepatitis B patients," they
continued. "Rapid on-treatment HBsAg decline of >
0.5 log10 IU/mL up to week 24 is highly predictive of future
HBsAg clearance."
Post-treatment
Outcomes
Finally,
Chinese researchers looked at sustained post-treatment outcomes
up to 2 years after patients completed treatment with telbivudine
(abstract 424).
The
analysis included 22 participants (17 HBeAg positive and
5 HBeAg negative) who received 600 mg/day telbivudine for
104 weeks.
Complete
response for initially HBeAg positive patients was defined
as undetectable HBV DNA, ALT normalization, and HBeAg seroconversion.
For initially HBeAg patients, completed response was defined
as undetectable HBV DNA and ALT normalization.
Patients
who demonstrated complete response for at least 24 weeks
could discontinue treatment and were followed for 2 years
post-treatment. Serum HBV DNA and HBsAg levels were assessed
at baseline, during treatment at weeks 24, 52, and 104,
and during post-treatment follow-up.
Results
|
At
treatment week 104, 50% of participants overall had
a complete response and discontinued telbivudine. |
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36%
of HBeAg positive patients achieved sustained virological
response (SVR), defined as continued undetectable HBV
DNA, ALT normalization, and HBeAg seroconversion after
2 years of follow-up. |
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A
significant positive correlation was observed between
on-treatment HBsAg levels and HBV DNA levels. |
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Patients
who achieved SVR had a greater mean reduction from baseline
in HBsAg levels while on treatment than non-sustained-responders.
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An
HBsAg level < 2 log10 IU/mL at treatment week 104
was highly predictive of SVR (negative predictive value
100%; positive predictive value 93%). |
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An
HBsAg decline of 0.8 log10 IU/mL at treatment week 24
also predicted of SVR (negative predictive value 75%;
positive predictive value 86%). |
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1
patient with an HBsAg decline > 3 log10 IU/mL at
treatment weeks 24, 52, 76, and 104 sero-reverted after
completed treatment. |
"On-treatment
serum HBsAg levels are highly predictive of SVR to telbivudine
at 2 years off treatment," the researchers concluded.
"Quantitative serum HBsAg levels at treatment weeks
24 and 52 were more predictive of SVR to telbivudine than
serum HBV DNA levels in these patients."
11/20/09
References
Y
Wang, S Thongsawat, EJ Gane, and others.
Efficacy and Safety Outcomes After 4 Years of Telbivudine
Treatment in Patients with Chronic Hepatitis B (CHB). 60th
Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD 2009). Boston. October 30-November
1, 2009. Abstract 482.
K
Wursthorn, M Jung, MP Manns, and others. Different Kinetics
of Serum HBsAg Decline in HBeAg-Positive vs HBeAg-Negative
Patients During 3 Years of Telbivudine Treatment in Chronic
Hepatitis B (CHB). 60th Annual Meeting of the American Association
for the Study of Liver Diseases (AASLD 2009). Boston. October
30-November 1, 2009. Abstract 487.
W
Cai, Q Xie, X Zhou, and others. On-treatment Serum HBsAg
Level at 2 Years: Strong Predictor of Sustained Virologic
Response to Telbivudine for up to 2 Years Off-treatment
in Chronic Hepatitis B Patients. 60th Annual Meeting of
the American Association for the Study of Liver Diseases
(AASLD 2009). Boston. October 30-November 1, 2009. Abstract
424.
