Data From GLOBE Trial Confirm Efficacy of Telbivudine for Chronic Hepatitis B
By
Liz Highleyman
In the wake of last week's FDA
approval of telbivudine (Tyzeka, formerly known as LdT) for the treatment
of chronic hepatitis B, researchers presented data from the pivotal GLOBE study
at the recent 57th Annual Meeting of the American Association for the Study of
Liver Diseases (AASLD) in Boston.
GLOBE is a randomized, blinded Phase
III trial comparing 600 mg/day oral telbivudine vs standard therapy with 100 mg/day
oral lamivudine. First-year results, reported in 2005, showed that telbivudine
demonstrated superior virological and clinical efficacy compared with lamivudine
(Epivir). Second-year data were presented at AASLD.
The intent-to-treat
(ITT) population consisted of 1367 chronic hepatitis B patients in 20 countries.
Study participants were HBsAg positive, had baseline HBV DNA greater than 6 log
copies/mL, ALT 1.3-10 x ULN, and compensated liver disease. Baseline characteristics
were similar in the telbivudine and lamivudine arms. Follow-up liver biopsies
were performed at 1 year, but were not repeated at 2 years.
2-Year Results
After 2 years, in an ITT analysis, significantly more patients in the telbivudine
arm achieved HBV DNA below 5 log with HBeAg loss or ALT normalization.
Telbivudine was superior on all direct measures of antiviral efficacy in both
HBeAg positive and HBeAg negative patients.
The rate of HBeAg loss was significantly higher for telbivudine in the sub-group
recommended for treatment by AASLD and Asia-Pacific guidelines, with baseline
ALT levels at least 2 x ULN.
ALT normalization was proportionally greater with telbivudine in both HBeAg positive
and HBeAg negative patients (P = 0.08).
Treatment failure was significantly more common with lamivudine in both groups.
Both
telbivudine and lamivudine were generally well-tolerated, with similar rates and
severity of adverse events.
Conclusion
In
conclusion, the researchers wrote, "During 2 years of treatment, telbivudine
produced significantly greater antiviral efficacy than lamivudine and was associated
with greater and better-maintained clinical efficacy, in HBeAg positive and HBeAg
negative patients with chronic hepatitis B.
HBeAg Positive
HBeAg Negative
Response
telbivudine
lamivudine
telbivudine
lamivudine
Number per arm (ITT)
458
463
222
224
Mean log HBV DNA decrease
5.7*
4.4
5.0*
4.2
% HBV DNA undetectable by PCR
54*
38
79*
53
% ALT normalization
67
61
75
67
% Therapeutic response
61*
47
74*
62
% HBeAg loss
34
29
-
-
% HBeAg loss (if baseline ALT ≥
2 x ULN)
40*
32
-
-
% HBeAgseroconversion
29
24
-
-
% Primary treatment failure‡
4*
12
0*
3
*P <
0.05, telbivudine vs lamivudine ‡HBV DNA never < 5 log copies/mLz Early
HBV Suppression Predicts 2-Year Outcomes
Based on another analysis
of GLOBE data, researchers reported on the relationship between early virological
suppression and outcomes after 2 years of treatment.
For this analysis,
2-year efficacy outcomes were assessed in relation to 4 categories of HBV DNA
level at Week 24 by Cobas Amplicor PCR:
undetectable (< 300 copies/mL);
detectable but less than 3 log copies/mL;
3-4 log copies/mL;
greater than 4 log copies/mL. Results
For all clinical and virological efficacy parameters, efficacy at 2 years was
incrementally proportional to HBV DNA level at Week 24.
More patients had undetectable HBV DNA at Week 24 in the telbivudine arm compared
with the lamivudine arm (57% vs 45%).
Fewer subjects receiving telbivudine had residual HBV DNA greater than 4 logs
at Week 24 (17% vs 27%, respectively).
Undetectable HBV DNA by PCR at Week 24 had high positive predictive values for
achieving all efficacy endpoints at Year 2.
Conversely, residual HBV DNA greater than 4 logs at Week 24 had high negative
predictive values for 2-yr efficacy outcomes.
Similar relationships between early response and 2-year outcomes were observed
with both telbivudine and lamivudine, although overall efficacy rates at 2 years
were proportionally higher with telbivudine.
Conclusion
The
researchers concluded that, "The magnitude of early viral suppression with
antiviral nucleosides influences subsequent efficacy outcomes for at least 2 years.
Two-year efficacy responses are high when HBV DNA is maximally suppressed at Week
24, consistent with the greater antiviral effects seen with telbivudine. The reduced
efficacy seen in pts with HBV DNA > 4 log at Week 24 suggests consideration
of intensified treatment. These relationships may be useful for optimizing patient
management."
Response
at Year 2
Serum HBV
DNA at Week 24 (copies/mL)
HBV DNA undetectable
<3 log
3-4 log
>4 log
HBeAg positive
Number
349
120
162
272
HBeAgseroconversion (%)
45
38
19
6
ALT normalization
(%)
79
76
63
43
HBV DNA undetectable
by PCR (%)
77
58
32
12
HBeAg negative
Number
335
38
40
30
ALT normalization
(%)
77
74
58
21
PCR-negative
(%)
74
66
40
10
Together, the data
from these 2 studies confirm the benefits of telbivudine over an extended course
of therapy. Unlike HCV, HBV must be treated over long periods and drug resistance
can develop months or years after starting antiviral agents. The second study
suggests that therapy for hepatitis B may go the way of hepatitis C treatment,
for which early response -- as early as Week 12 or even Week 4 -- is used to predict
response and adjust (or discontinue) therapy. University of, Hong Kong;
Middlemore Hospital, Auckland, New Zealand; Chang Gung University and Memorial
Hospital, Taipei, Taiwan; Chiang Mai University, Chiang Mai, Thailand; Military
Medical University, Chongqing, China; Zhejiang University College of Medicine
, Hangzhou, China; Toronto Western Hospital, Toronto, ON, Canada; Albert Ludwigs
Universität, Freiburg, Germany; Sutter Health, San Francisco, CA; Saarland
University Hospital, Homburg, Germany; Saint Louis University, St. Louis, MO;
UCLA School of Medicine, Los Angeles, CA; Institute of Hepatology, University
College, London, UK; National University Hospital, Singapore; Bundang CHA Hospital,
Gyeonggi-Do, South Korea; Idenix Pharmaceuticals, Cambridge, MA.
11/03/06 References
C
Lai, E Gane, C Hsu, and others. Two-Year Results from the GLOBE Trial in Patients
with Hepatitis B: Greater Clinical and Antiviral Efficacy for Telbivudine (LdT)
vs. Lamivudine. 57th AASLD. October 27-31, 2006. Boston, MA. Abstract 91.
A
DiBisceglie, C Lai, E Gane, and others. Telbivudine GLOBE Trial: Maximal Early
HBV Suppression is Predictive of Optimal Two-Year Efficacy in Nucleoside-Treated
Hepatitis B Patients. 57th AASLD. October 27-31, 2006. Boston, MA. Abstract 112.
After 2 years, in an ITT analysis, significantly more patients in the telbivudine
arm achieved HBV DNA below 5 log with HBeAg loss or ALT normalization.
